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Open AccessReview The Fetus Can Teach Us: Oxygen and the Pulmonary Vasculature

by Payam Vali and Satyan Lakshminrusimha

Children 2017, 4(8), 67; doi:10.3390/children4080067 (registering DOI)

Received: 26 May 2017 / Revised: 22 July 2017 / Accepted: 31 July 2017 / Published: 3 August 2017

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Abstract

Neonates suffering from pulmonary hypertension of the newborn (PPHN) continue to represent an important proportion of patients requiring intensive neonatal care, and have an increased risk of morbidity and mortality. The human fetus has evolved to maintain a high pulmonary vascular resistance (PVR)

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Neonates suffering from pulmonary hypertension of the newborn (PPHN) continue to represent an important proportion of patients requiring intensive neonatal care, and have an increased risk of morbidity and mortality. The human fetus has evolved to maintain a high pulmonary vascular resistance (PVR) in utero to allow the majority of the fetal circulation to bypass the lungs, which do not participate in gas exchange, towards the low resistance placenta. At birth, oxygen plays a major role in decreasing PVR to enhance pulmonary blood flow and establish the lungs as the organ of gas exchange. The failure of PVR to fall following birth results in PPHN, and oxygen remains the mainstay therapeutic intervention in the management of PPHN. Knowledge gaps on what constitutes the optimal oxygenation target leads to a wide variation in practices, and often leads to excessive oxygen use. Owing to the risk of oxygen toxicity, avoiding hyperoxemia is as important as avoiding hypoxemia in the management of PPHN. Current evidence supports maintaining arterial oxygen tension in the range of 50–80 mm Hg, and oxygen saturation between 90–97% in term infants with hypoxemic respiratory failure. Clinical studies evaluating the optimal oxygenation in the treatment of PPHN will be enthusiastically awaited. Full article

(This article belongs to the Special Issue New Trend in Pediatric Cardiology: Pulmonary Hypertension)

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Open AccessReview Persistent Pulmonary Hypertension in the Newborn

by Bobby Mathew and Satyan Lakshminrusimha

Children 2017, 4(8), 63; doi:10.3390/children4080063

Received: 2 June 2017 / Revised: 18 July 2017 / Accepted: 25 July 2017 / Published: 28 July 2017

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Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth due to delay or impairment in the normal fall in pulmonary vascular resistance (PVR) that occurs following birth. The fetus is in a state of physiological pulmonary

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Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth due to delay or impairment in the normal fall in pulmonary vascular resistance (PVR) that occurs following birth. The fetus is in a state of physiological pulmonary hypertension. In utero, the fetus receives oxygenated blood from the placenta through the umbilical vein. At birth, following initiation of respiration, there is a sudden precipitous fall in the PVR and an increase of systemic vascular resistance (SVR) due to the removal of the placenta from circulation. There is dramatic increase in pulmonary blood flow with a decrease in, and later reversal of shunts at the foramen ovale and ductus arteriosus. The failure of this normal physiological pulmonary transition leads to the syndrome of PPHN. PPHN presents with varying degrees of hypoxemic respiratory failure. Survival of infants with PPHN has significantly improved with the use of gentle ventilation, surfactant and inhaled nitric oxide (iNO). PPHN is associated with significant mortality and morbidity among survivors. Newer agents that target different enzymatic pathways in the vascular smooth muscle are in different stages of development and testing. Further research using these agents is likely to further reduce morbidity and mortality associated with PPHN. Full article

(This article belongs to the Special Issue New Trend in Pediatric Cardiology: Pulmonary Hypertension)

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Open AccessArticle Adjuvantation of Pulmonary-Administered Influenza Vaccine with GPI-0100 Primarily Stimulates Antibody Production and Memory B Cell Proliferation

by Harshad P. Patil, José Herrera Rodriguez, Jacqueline de Vries-Idema, Tjarko Meijerhof, Henderik W. Frijlink, Wouter L. J. Hinrichs and Anke Huckriede

Vaccines 2017, 5(3), 19; doi:10.3390/vaccines5030019

Received: 12 April 2017 / Revised: 19 June 2017 / Accepted: 21 July 2017 / Published: 27 July 2017

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Abstract

Adjuvants are key components in vaccines, they help in reducing the required antigen dose but also modulate the phenotype of the induced immune response. We previously showed that GPI-0100, a saponin-derived adjuvant, enhances antigen-specific mucosal and systemic antibody responses to influenza subunit and

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Adjuvants are key components in vaccines, they help in reducing the required antigen dose but also modulate the phenotype of the induced immune response. We previously showed that GPI-0100, a saponin-derived adjuvant, enhances antigen-specific mucosal and systemic antibody responses to influenza subunit and whole inactivated influenza virus (WIV) vaccine administered via the pulmonary route. However, the impact of the GPI-0100 dose on immune stimulation and the immune mechanisms stimulated by GPI-0100 along with antigen are poorly understood. Therefore, in this study we immunized C57BL/6 mice via the pulmonary route with vaccine consisting of WIV combined with increasing amounts of GPI-0100, formulated as a dry powder. Adjuvantation of WIV enhanced influenza-specific mucosal and systemic immune responses, with intermediate doses of 5 and 7.5 μg GPI-0100 being most effective. The predominant antibody subtype induced by GPI-0100-adjuvanted vaccine was IgG1. Compared to non-adjuvanted vaccine, GPI-0100-adjuvanted WIV vaccine gave rise to higher numbers of antigen-specific IgA- but not IgG-producing B cells in the lungs along with better mucosal and systemic memory B cell responses. The GPI-0100 dose was negatively correlated with the number of influenza-specific IFNγ- and IL17-producing T cells and positively correlated with the number of IL4-producing T cells observed after immunization and challenge. Overall, our results show that adjuvantation of pulmonary-delivered WIV with GPI-0100 mostly affects B cell responses and effectively induces B cell memory. Full article

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Open AccessArticle Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Fetal Pulmonary Circulation: An Experimental Study in Fetal Lambs

by Dyuti Sharma, Estelle Aubry, Thavarak Ouk, Ali Houeijeh, Véronique Houfflin-Debarge, Rémi Besson, Philippe Deruelle and Laurent Storme

Nutrients 2017, 9(7), 761; doi:10.3390/nu9070761

Received: 23 May 2017 / Revised: 7 July 2017 / Accepted: 10 July 2017 / Published: 16 July 2017

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Abstract

Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n-3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep

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Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n-3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep and in fetal pulmonary arterial rings. Methods: At 128 days of gestation, catheters were placed surgically in fetal systemic and pulmonary circulation, and a Doppler probe around the left pulmonary artery (LPA). Pulmonary arterial pressure and LPA flow were measured while infusing EPA or DHA for 120 min to the fetus, to compute pulmonary vascular resistance (PVR). The dose effects of EPA or DHA were studied in vascular rings pre-constricted with serotonin. Rings treated with EPA were separated into three groups: E+ (intact endothelium), E− (endothelium stripped) and LNA E+ (pretreatment of E+ rings with l-nitro-arginine). Results: EPA, but not DHA, induced a significant and prolonged 25% drop in PVR (n = 8, p < 0.001). Incubation of vascular rings with EPA (100 µM) caused a maximum relaxation of 60% in the E+ (n = 6), whereas vessel tone did not change in the E− (n = 6, p < 0.001). The vascular effects of EPA were significantly decreased in LNA E+ (n = 6). Incubation with DHA resulted in only a mild relaxation at the highest concentration of DHA (300 µM) compared to E+. Conclusions: EPA induces a sustained pulmonary vasodilatation in fetal lambs. This effect is endothelium- and dose-dependent and involves nitric oxide (NO) production. We speculate that EPA supplementation may improve pulmonary circulation in clinical conditions with PPHN. Full article

(This article belongs to the Special Issue Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Health)

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Open AccessReview Reactive Oxygen and Nitrogen Species in the Development of Pulmonary Hypertension

by David J.R. Fulton, Xueyi Li, Zsuzsanna Bordan, Stephen Haigh, Austin Bentley, Feng Chen and Scott A. Barman

Antioxidants 2017, 6(3), 54; doi:10.3390/antiox6030054

Received: 18 May 2017 / Revised: 29 June 2017 / Accepted: 1 July 2017 / Published: 6 July 2017

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Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature that involves the loss of endothelial function together with inappropriate smooth muscle cell growth, inflammation, and fibrosis. These changes underlie a progressive remodeling of blood vessels that alters flow and increases

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Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature that involves the loss of endothelial function together with inappropriate smooth muscle cell growth, inflammation, and fibrosis. These changes underlie a progressive remodeling of blood vessels that alters flow and increases pulmonary blood pressure. Elevated pressures in the pulmonary artery imparts a chronic stress on the right ventricle which undergoes compensatory hypertrophy but eventually fails. How PAH develops remains incompletely understood and evidence for the altered production of reactive oxygen and nitrogen species (ROS, RNS respectively) in the pulmonary circulation has been well documented. There are many different types of ROS and RNS, multiple sources, and collective actions and interactions. This review summarizes past and current knowledge of the sources of ROS and RNS and how they may contribute to the loss of endothelial function and changes in smooth muscle proliferation in the pulmonary circulation. Full article

(This article belongs to the Special Issue ROS Derived from NADPH Oxidase (NOX) in Angiogenesis)

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Open AccessArticle A Novel Therapeutic Approach in the Treatment of Pulmonary Arterial Hypertension: Allium ursinum Liophylisate Alleviates Symptoms Comparably to Sildenafil

by Mariann Bombicz, Daniel Priksz, Balazs Varga, Andrea Kurucz, Attila Kertész, Akos Takacs, Aniko Posa, Rita Kiss, Zoltan Szilvassy and Bela Juhasz

Int. J. Mol. Sci. 2017, 18(7), 1436; doi:10.3390/ijms18071436

Received: 9 June 2017 / Revised: 23 June 2017 / Accepted: 27 June 2017 / Published: 4 July 2017

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Abstract

Right-sided heart failure—often caused by elevated pulmonary arterial pressure—is a chronic and progressive condition with particularly high mortality rates. Recent studies and our current findings suggest that components of Wild garlic (Allium ursinum, AU) may play a role in reducing blood

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Right-sided heart failure—often caused by elevated pulmonary arterial pressure—is a chronic and progressive condition with particularly high mortality rates. Recent studies and our current findings suggest that components of Wild garlic (Allium ursinum, AU) may play a role in reducing blood pressure, inhibiting angiotensin-converting enzyme (ACE), as well as improving right ventricle function in rabbit models with heart failure. We hypothesize that AU may mitigate cardiovascular damage caused by pulmonary arterial hypertension (PAH) and has value in the supplementary treatment of the complications of the disease. In this present investigation, PAH was induced by a single dose of monocrotaline (MCT) injection in Sprague-Dawley rats, and animals were divided into 4 treatment groups as follows: I. healthy control animals (Control group); II. pulmonary hypertensive rats (PAH group); III. pulmonary hypertensive rats + daily sildenafil treatment (Sildenafil group); and IV. pulmonary hypertensive rats + Wild garlic liophylisate-enriched chow (WGLL group), for 8 weeks. Echocardiographic measurements were obtained on the 0 and 8 weeks with fundamental and Doppler imaging. Isolated working heart method was used to determinate cardiac functions ex vivo after thoracotomy on the 8th week. Histological analyses were carried out on excised lung samples, and Western blot technique was used to determine Phosphodiesterase type 5 enzyme (PDE5) expression in both myocardial and pulmonary tissues. Our data demonstrate that right ventricle function measured by echocardiography was deteriorated in PAH animals compared to controls, which was counteracted by AU treatment. Isolated working heart measurements showed elevated aortic flow in WGLL group compared to PAH animals. Histological analysis revealed dramatic increase in medial wall thickness of pulmonary arteries harvested from PAH animals, but arteries of animals in sildenafil- and WGLL-treated groups showed physiological status. Our results suggest that bioactive compounds in Allium ursinum could have beneficial effects in pulmonary hypertension. Full article

(This article belongs to the Special Issue Correlation between Nutrition, Oxidative Stress and Disease)

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Open AccessArticle Discrimination of Aortic and Pulmonary Components from the Second Heart Sound Using Respiratory Modulation and Measurement of Respiratory Split

by Hong Tang, Huaming Chen and Ting Li

Appl. Sci. 2017, 7(7), 690; doi:10.3390/app7070690

Received: 15 June 2017 / Revised: 3 July 2017 / Accepted: 3 July 2017 / Published: 4 July 2017

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Abstract

The second heart sound consists of aortic and pulmonary components. Analysis on the changes of the second heart sound waveform in respiration shows that the aortic component has little variation and the delay of the pulmonary component is modulated by respiration. This paper

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The second heart sound consists of aortic and pulmonary components. Analysis on the changes of the second heart sound waveform in respiration shows that the aortic component has little variation and the delay of the pulmonary component is modulated by respiration. This paper proposes a novel model to discriminate the aortic and pulmonary components using respiratory modulation. It is found that the aortic component could be simply extracted by averaging the second heart sounds over respiratory phase, and the pulmonary component could be extracted by subtraction. Hence, the split is measured by the timing difference of the two components. To validate the measurement, the method is applied to simulated second heart sounds with known varying splits. The simulation results show that the aortic and pulmonary components can be successfully extracted and the measured splits are close to the predefined splits. The method is further evaluated by data collected from 12 healthy subjects. Experimental results show that the respiratory split can be accurately measured. The minimum split generally occurs at the end of expiration and the split value is about 20 ms. Meanwhile, the maximum split is about 50 ms at the end of inspiration. Both the trend of split varying with respect to respiratory phase and the numerical range of split varying are comparable to the results disclosed by previous physiologists. The proposed method is compared to the two previous well known methods. The most attractive advantage of the proposed method is much less complexity. This method has potential applications in monitoring heart hemodynamic response to respiration. Full article

(This article belongs to the Special Issue Smart Healthcare)

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Open AccessReview Chronic Respiratory Infection in Patients with Chronic Obstructive Pulmonary Disease: What Is the Role of Antibiotics?

by Marc Miravitlles and Antonio Anzueto

Int. J. Mol. Sci. 2017, 18(7), 1344; doi:10.3390/ijms18071344

Received: 31 March 2017 / Revised: 24 May 2017 / Accepted: 3 June 2017 / Published: 23 June 2017

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Abstract

Chronic infections are associated with exacerbation in patients with chronic obstructive pulmonary disease (COPD). The major objective of the management of these patients is the prevention and effective treatment of exacerbations. Patients that have increased sputum production, associated with purulence and worsening shortness

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Chronic infections are associated with exacerbation in patients with chronic obstructive pulmonary disease (COPD). The major objective of the management of these patients is the prevention and effective treatment of exacerbations. Patients that have increased sputum production, associated with purulence and worsening shortness of breath, are the ones that will benefit from antibiotic therapy. It is important to give the appropriate antibiotic therapy to prevent treatment failure, relapse, and the emergence of resistant pathogens. In some patients, systemic corticosteroids are also indicated to improve symptoms. In order to identify which patients are more likely to benefit from these therapies, clinical guidelines recommend stratifying patients based on their risk factor associated with poor outcome or recurrence. It has been identified that patients with more severe disease, recurrent infection and presence of purulent sputum are the ones that will be more likely to benefit from this therapy. Another approach related to disease prevention could be the use of prophylactic antibiotics during steady state condition. Some studies have evaluated the continuous or the intermittent use of antibiotics in order to prevent exacerbations. Due to increased bacterial resistance to antibiotics and the presence of side effects, several antibiotics have been developed to be nebulized for both treatment and prevention of acute exacerbations. There is a need to design long-term studies to evaluate these interventions in the natural history of the disease. The purpose of this publication is to review our understanding of the role of bacterial infection in patients with COPD exacerbation, the role of antibiotics, and future interventions. Full article

(This article belongs to the Special Issue Lung Diseases: Chronic Respiratory Infections)

Open AccessArticle Investigation of Acute Pulmonary Deficits Associated with Biomass Fuel Cookstove Emissions in Rural Bangladesh

by Danielle N. Medgyesi, Heather A. Holmes and Jeff E. Angermann

Int. J. Environ. Res. Public Health 2017, 14(6), 641; doi:10.3390/ijerph14060641

Received: 4 April 2017 / Revised: 20 May 2017 / Accepted: 9 June 2017 / Published: 15 June 2017

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Abstract

The use of solid biomass fuels in cookstoves has been associated with chronic health impacts that disproportionately affect women worldwide. Solid fuel stoves that use wood, plant matter, and cow dung are commonly used for household cooking in rural Bangladesh. This study investigates

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The use of solid biomass fuels in cookstoves has been associated with chronic health impacts that disproportionately affect women worldwide. Solid fuel stoves that use wood, plant matter, and cow dung are commonly used for household cooking in rural Bangladesh. This study investigates the immediate effects of acute elevated cookstove emission exposures on pulmonary function. Pulmonary function was measured with spirometry before and during cooking to assess changes in respiratory function during exposure to cookstove emissions for 15 females ages 18–65. Cookstove emissions were characterized using continuous measurements of particulate matter (PM_2.5—aerodynamic diameter <2.5 μm) concentrations at a 1 s time resolution for each household. Several case studies were observed where women ≥40 years who had been cooking for ≥25 years suffered from severe pulmonary impairment. Forced expiratory volume in one second over forced vital capacity (FEV1/FVC) was found to moderately decline (p = 0.06) during cooking versus non-cooking in the study cohort. The study found a significant (α < 0.05) negative association between 3- and 10-min maximum PM_2.5 emissions during cooking and lung function measurements of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC obtained during cooking intervals. This study found that exposure to biomass burning emissions from solid fuel stoves- associated with acute elevated PM_2.5 concentrations- leads to a decrease in pulmonary function, although further research is needed to ascertain the prolonged (e.g., daily, for multiple years) impacts of acute PM_2.5 exposure on immediate and sustained respiratory impairment. Full article

(This article belongs to the Special Issue Indoor Air Quality and Health 2016)

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Open AccessArticle Innate and Adaptive Immune Defects in Chronic Pulmonary Aspergillosis

by Felix Bongomin, Chris Harris, Philip Foden, Chris Kosmidis and David W. Denning

J. Fungi 2017, 3(2), 26; doi:10.3390/jof3020026

Received: 10 April 2017 / Revised: 4 May 2017 / Accepted: 8 May 2017 / Published: 29 May 2017

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Abstract

We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8,

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We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were included. Eighty-four (58%) patients had lymphopenia. Six (4%) patients had lymphopenia in all five CD variables. There were 62 (43%) patients with low CD56 and 62 (43%) patients with low CD19. Ten (7%) patients had isolated CD19 lymphopenia, 18 (13%) had isolated CD56 lymphopenia, and 15 (10%) had combined CD19 and CD56 lymphopenia only. Forty-eight (33%) patients had low CD3 and 46 (32%) had low CD8 counts. Twenty-five (17%) patients had low CD4, 15 (10%) of whom had absolute CD4 counts <200/μL. Multivariable logistic regression showed associations between: low CD19 and pulmonary sarcoidosis (Odds Ratio (OR), 5.53; 95% Confidence Interval (CI), 1.43–21.33; p = 0.013), and emphysema (OR, 4.58; 95% CI; 1.36–15.38; p = 0.014), low CD56 and no bronchiectasis (OR, 0.27; 95% CI, 0.10–0.77; p = 0.014), low CD3 and both multicavitary CPA disease (OR, 2.95; 95% CI, 1.30–6.72; p = 0.010) and pulmonary sarcoidosis (OR, 4.94; 95% CI, 1.39–17.57; p = 0.014). Several subtle immune defects are found in CPA. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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Open AccessFeature PaperReview Emerging Metabolic Therapies in Pulmonary Arterial Hypertension

by Lloyd D. Harvey and Stephen Y. Chan

J. Clin. Med. 2017, 6(4), 43; doi:10.3390/jcm6040043

Received: 15 February 2017 / Revised: 28 March 2017 / Accepted: 29 March 2017 / Published: 4 April 2017

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Abstract

Pulmonary hypertension (PH) is an enigmatic vascular disorder characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in pressure overload, dysfunction, and failure of the right ventricle. Current medications for PH do not reverse or prevent disease progression, and current

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Pulmonary hypertension (PH) is an enigmatic vascular disorder characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in pressure overload, dysfunction, and failure of the right ventricle. Current medications for PH do not reverse or prevent disease progression, and current diagnostic strategies are suboptimal for detecting early-stage disease. Thus, there is a substantial need to develop new diagnostics and therapies that target the molecular origins of PH. Emerging investigations have defined metabolic aberrations as fundamental and early components of disease manifestation in both pulmonary vasculature and the right ventricle. As such, the elucidation of metabolic dysregulation in pulmonary hypertension allows for greater therapeutic insight into preventing, halting, or even reversing disease progression. This review will aim to discuss (1) the reprogramming and dysregulation of metabolic pathways in pulmonary hypertension; (2) the emerging therapeutic interventions targeting these metabolic pathways; and (3) further innovation needed to overcome barriers in the treatment of this devastating disease. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Pulmonary Arterial Hypertension)

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Open AccessFeature PaperReview The Changing Landscape of Pulmonary Arterial Hypertension in the Adult with Congenital Heart Disease

by Alexandra C. van Dissel, Barbara J. M. Mulder and Berto J. Bouma

J. Clin. Med. 2017, 6(4), 40; doi:10.3390/jcm6040040

Received: 31 January 2017 / Revised: 9 March 2017 / Accepted: 23 March 2017 / Published: 30 March 2017

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Abstract

Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a common type of pulmonary arterial hypertension (PAH) and a frequent complication of congenital heart disease (CHD). PAH-CHD represents a heterogeneous patient population and it is important to distinguish between the underlying cardiac

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Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a common type of pulmonary arterial hypertension (PAH) and a frequent complication of congenital heart disease (CHD). PAH-CHD represents a heterogeneous patient population and it is important to distinguish between the underlying cardiac defects considering the prognostic and therapeutic implications. Improved interventional techniques have enabled repair or palliation of most cardiac defects, though a substantial number of patients remain at high risk for PAH after closure. Traditionally, the treatment and management of PAH-CHD patients has been limited to palliative and supportive care, and based on expert opinion rather than clinical trials. Recently, however, the availability of advanced PAH-specific treatment has opened up a new field for the clinical management of this condition. Nevertheless, there is limited evidence on the optimal therapeutic approach for PAH-CHD. Herein, we discuss the current and novel therapeutic options for PAH-CHD as well as highlight several challenges in the clinical management at present. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Pulmonary Arterial Hypertension)

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Open AccessReview Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives

by Palma Lamonaca, Giulia Prinzi, Aliaksei Kisialiou, Vittorio Cardaci, Massimo Fini and Patrizia Russo

Mar. Drugs 2017, 15(3), 81; doi:10.3390/md15030081

Received: 22 November 2016 / Revised: 23 February 2017 / Accepted: 15 March 2017 / Published: 20 March 2017

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Abstract

Metabolic disorder has been frequently observed in chronic obstructive pulmonary disease (COPD) patients. However, the exact correlation between obesity, which is a complex metabolic disorder, and COPD remains controversial. The current study summarizes a variety of drugs from marine sources that have anti-obesity

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Metabolic disorder has been frequently observed in chronic obstructive pulmonary disease (COPD) patients. However, the exact correlation between obesity, which is a complex metabolic disorder, and COPD remains controversial. The current study summarizes a variety of drugs from marine sources that have anti-obesity effects and proposed potential mechanisms by which lung function can be modulated with the anti-obesity activity. Considering the similar mechanism, such as inflammation, shared between obesity and COPD, the study suggests that marine derivatives that act on the adipose tissues to reduce inflammation may provide beneficial therapeutic effects in COPD subjects with high body mass index (BMI). Full article

(This article belongs to the Special Issue Marine Natural Products that Target Metabolic Disorders)

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Open AccessReview Response to Pulmonary Rehabilitation in Older People with Physical Frailty, Sarcopenia and Chronic Lung Disease

by Luke Attwell and Michael Vassallo

Geriatrics 2017, 2(1), 9; doi:10.3390/geriatrics2010009

Received: 26 October 2016 / Revised: 4 January 2017 / Accepted: 20 January 2017 / Published: 22 January 2017

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Abstract

Frailty and sarcopenia are two important clinical syndromes associated with the ageing process, with a high risk of morbidity and mortality. Patients with chronic disease have been shown to have an accelerated decline into a frail state, with patients with both chronic lung

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Frailty and sarcopenia are two important clinical syndromes associated with the ageing process, with a high risk of morbidity and mortality. Patients with chronic disease have been shown to have an accelerated decline into a frail state, with patients with both chronic lung disease and frailty having a higher mortality than those with frailty alone. Pulmonary rehabilitation has been found to be an effective intervention in patients with chronic obstructive pulmonary disease (COPD), yet the effect of frailty on this as intervention remains unclear. A narrative literature search of PubMed, Medline complete and the Cochrane library was performed by the reviewers using predefined criteria. Only 3 studies met the selection criteria and were reviewed. These studies highlighted that, although completion rates are lower in patients with both COPD and frailty, pulmonary rehabilitation remains effective as an intervention in this subgroup of patients, with up to 61% of frail patients no longer meeting frailty criteria after completion of a pulmonary rehabilitation programme. Full article

(This article belongs to the Special Issue Frailty and Sarcopenia in Old Age)

Open AccessReview A Review of Targeted Pulmonary Arterial Hypertension-Specific Pharmacotherapy

by Ali Ataya, Jessica Cope and Hassan Alnuaimat

J. Clin. Med. 2016, 5(12), 114; doi:10.3390/jcm5120114

Received: 9 September 2016 / Revised: 22 November 2016 / Accepted: 29 November 2016 / Published: 6 December 2016

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Abstract

Significant advances in the understanding of the pathophysiology of pulmonary arterial hypertension over the past two decades have led to the development of targeted therapies and improved patient outcomes. Currently, a broad armamentarium of pulmonary arterial hypertension-specific drugs exists to assist in the

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Significant advances in the understanding of the pathophysiology of pulmonary arterial hypertension over the past two decades have led to the development of targeted therapies and improved patient outcomes. Currently, a broad armamentarium of pulmonary arterial hypertension-specific drugs exists to assist in the treatment of this complex disease state. In this manuscript, we provide a comprehensive review of the current Food and Drug Administration (FDA)-approved pulmonary arterial hypertension-specific therapies, and their supporting evidence for adults, targeting the nitric oxide, soluble guanylate cyclase, endothelin, and prostacyclin pathways. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Pulmonary Arterial Hypertension)

Open AccessReview Pulmonary Hypertension Due to Common Respiratory Conditions: Classification, Evaluation and Management Strategies

by Daniel G. Fein, Ali N. Zaidi and Roxana Sulica

J. Clin. Med. 2016, 5(9), 75; doi:10.3390/jcm5090075

Received: 2 June 2016 / Revised: 11 August 2016 / Accepted: 22 August 2016 / Published: 26 August 2016

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Abstract

Pulmonary hypertension (PH) due to chronic respiratory disease and/or hypoxia is classified as World Health Organization (WHO) Group III pulmonary hypertension. The patients most commonly encountered in clinical practice with group III PH include those with chronic obstructive lung disease (COPD), diffuse parenchymal

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Pulmonary hypertension (PH) due to chronic respiratory disease and/or hypoxia is classified as World Health Organization (WHO) Group III pulmonary hypertension. The patients most commonly encountered in clinical practice with group III PH include those with chronic obstructive lung disease (COPD), diffuse parenchymal lung disease, and sleep-disordered breathing. The purpose of this review is to outline the variable clinical significance of pulmonary hypertension in the most common pulmonary disease states and how a clinician may approach the management of these patients. Full article

(This article belongs to the Special Issue Chronic Respiratory Diseases)

Open AccessArticle Physical Activity and Exertional Desaturation Are Associated with Mortality in Idiopathic Pulmonary Fibrosis

by Baruch Vainshelboim, Mordechai Reuven Kramer, Shimon Izhakian, Ricardo M. Lima and Jose Oliveira

J. Clin. Med. 2016, 5(8), 73; doi:10.3390/jcm5080073

Received: 3 July 2016 / Revised: 1 August 2016 / Accepted: 15 August 2016 / Published: 18 August 2016

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that manifests in hypoxemia, inactivity, and poor prognosis. This study aimed to assess the prognostic role of physical activity (PA) and exertional desaturation (ED) with mortality in IPF. At baseline, 34 IPF patients (68

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Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that manifests in hypoxemia, inactivity, and poor prognosis. This study aimed to assess the prognostic role of physical activity (PA) and exertional desaturation (ED) with mortality in IPF. At baseline, 34 IPF patients (68 (50–81) years) were interviewed using the International Physical Activity Questionnaire (IPAQ), and SpO₂ was assessed pre to post 6-min walking test (∆SpO₂). Patients were prospectively followed up for 40 months. Receiver operating characteristics curve analysis determined cut-off points associated with mortality, and Cox proportional hazard ratio (HR) were conducted. Thresholds for increased mortality risk in IPF patients were determined as IPAQ ≤ 417 metabolic equivalent task (METS)-min/week, p = 0.004 (HR; 9.7, CI 95% (1.3–71.9), p = 0.027), and ∆SpO₂ ≥ 10%, p = 0.002, (HR; 23.3, CI 95% (1.5–365), p = 0.025). This study demonstrated a significant association of PA and ED with mortality in IPF patients. The findings emphasize the clinical importance of PA and ED assessments to aid in IPF risk stratification, prognosis prediction, and in providing early appropriate treatments, such as pulmonary rehabilitation, PA consultation, oxygen supplementation, and lung transplantation referral. These results underscore that even low levels of PA corresponding to 100–105 min/week were associated with a reduced mortality risk and better survival in IPF. Full article

(This article belongs to the Special Issue Chronic Respiratory Diseases)

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Open AccessArticle The Effects of Aquaporin-1 in Pulmonary Edema Induced by Fat Embolism Syndrome

by Yiwei Zhang, Kun Tian, Yan Wang, Rong Zhang, Jiawei Shang, Wei Jiang and Aizhong Wang

Int. J. Mol. Sci. 2016, 17(7), 1183; doi:10.3390/ijms17071183

Received: 4 June 2016 / Revised: 11 July 2016 / Accepted: 15 July 2016 / Published: 21 July 2016

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Abstract

This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs).

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This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). In vivo, edema was more serious in FES mice compared with the control group. The expression of AQP1 and the wet-to-dry lung weight ratio (W/D) in the FES group were significantly increased compared with the control group. At the same time, inhibition of AQP1 decreased the pathological damage resulting from pulmonary edema. Then we performed a study in vitro to investigate whether AQP1 was induced by FFA release in FES. The mRNA and protein level of AQP1 were increased by FFAs in a dose- and time-dependent manner in PMVECs. In addition, the up-regulation of AQP1 was blocked by the inhibitor of p38 kinase, implicating the p38 MAPK pathway as involved in the FFA-induced AQP1 up-regulation in PMVECs. Our results demonstrate that AQP1 may play important roles in pulmonary edema induced by FES and can be regarded as a new therapy target for treatment of pulmonary edema induced by FES. Full article

(This article belongs to the Special Issue Aquaporin)

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Open AccessReview DNA Damage and Pulmonary Hypertension

by Benoît Ranchoux, Jolyane Meloche, Roxane Paulin, Olivier Boucherat, Steeve Provencher and Sébastien Bonnet

Int. J. Mol. Sci. 2016, 17(6), 990; doi:10.3390/ijms17060990

Received: 5 April 2016 / Revised: 1 June 2016 / Accepted: 16 June 2016 / Published: 22 June 2016

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Abstract

Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries,

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Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, related to endothelial cell dysfunction and vascular cell proliferation, which leads to an increased pulmonary vascular resistance, right ventricular hypertrophy, and right heart failure. Although the primary trigger of PAH remains unknown, oxidative stress and inflammation have been shown to play a key role in the development and progression of vascular remodeling. These factors are known to increase DNA damage that might favor the emergence of the proliferative and apoptosis-resistant phenotype observed in PAH vascular cells. High levels of DNA damage were reported to occur in PAH lungs and remodeled arteries as well as in animal models of PH. Moreover, recent studies have demonstrated that impaired DNA-response mechanisms may lead to an increased mutagen sensitivity in PAH patients. Finally, PAH was linked with decreased breast cancer 1 protein (BRCA1) and DNA topoisomerase 2-binding protein 1 (TopBP1) expression, both involved in maintaining genome integrity. This review aims to provide an overview of recent evidence of DNA damage and DNA repair deficiency and their implication in PAH pathogenesis. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)

Open AccessReview Chronic Pulmonary Aspergillosis—Where Are We? and Where Are We Going?

by Gemma E. Hayes and Lilyann Novak-Frazer

J. Fungi 2016, 2(2), 18; doi:10.3390/jof2020018

Received: 20 March 2016 / Revised: 19 May 2016 / Accepted: 1 June 2016 / Published: 7 June 2016

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Abstract

Chronic pulmonary aspergillosis (CPA) is estimated to affect 3 million people worldwide making it an under recognised, but significant health problem across the globe, conferring significant morbidity and mortality. With variable disease forms, high levels of associated respiratory co-morbidity, limited therapeutic options and

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Chronic pulmonary aspergillosis (CPA) is estimated to affect 3 million people worldwide making it an under recognised, but significant health problem across the globe, conferring significant morbidity and mortality. With variable disease forms, high levels of associated respiratory co-morbidity, limited therapeutic options and prolonged treatment strategies, CPA is a challenging disease for both patients and healthcare professionals. CPA can mimic smear-negative tuberculosis (TB), pulmonary histoplasmosis or coccidioidomycosis. Cultures for Aspergillus are usually negative, however, the detection of Aspergillus IgG is a simple and sensitive test widely used in diagnosis. When a fungal ball/aspergilloma is visible radiologically, the diagnosis has been made late. Sometimes weight loss and fatigue are predominant symptoms; pyrexia is rare. Despite the efforts of the mycology community, and significant strides being taken in optimising the care of these patients, much remains to be learnt about this patient population, the disease itself and the best use of available therapies, with the development of new therapies being a key priority. Here, current knowledge and practices are reviewed, and areas of research priority highlighted. Full article

(This article belongs to the Special Issue Aspergillus fumigatus: From Diagnosis to Therapy)

Open AccessReview Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

by Jane A. Leopold and Bradley A. Maron

Int. J. Mol. Sci. 2016, 17(5), 761; doi:10.3390/ijms17050761

Received: 7 March 2016 / Revised: 1 April 2016 / Accepted: 8 April 2016 / Published: 18 May 2016

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Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy,

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Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype. Full article

(This article belongs to the Special Issue Molecular Research on Hypertension)

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Open AccessArticle Association between Outdoor Fungal Concentrations during Winter and Pulmonary Function in Children with and without Asthma

by Masanari Watanabe, Hisashi Noma, Jun Kurai, Degejirihu Hantan, Naoto Burioka, Sachiko Nakamoto, Hiroyuki Sano, Jumpei Taniguchi and Eiji Shimizu

Int. J. Environ. Res. Public Health 2016, 13(5), 452; doi:10.3390/ijerph13050452

Received: 20 March 2016 / Revised: 25 April 2016 / Accepted: 25 April 2016 / Published: 28 April 2016

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Abstract

Outdoor fungi are important components of airborne particulate matter (PM). However, the associations between pulmonary function and outdoor fungi are less well known compared to other airborne PM constituents. The objective of this study was to investigate the association between outdoor fungi and

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Outdoor fungi are important components of airborne particulate matter (PM). However, the associations between pulmonary function and outdoor fungi are less well known compared to other airborne PM constituents. The objective of this study was to investigate the association between outdoor fungi and pulmonary function in children. Morning peak expiratory flow (PEF) rates were measured daily in 339 schoolchildren (including 36 with asthma), aged 10 to 12, 2 to 27 February 2015. Airborne PM was collected on filters, using a high volume air sampler, each day during the study period. The daily concentration of outdoor fungi-associated PM was calculated using a culture-based method. A linear mixed model was used to estimate the association between PEF values and daily concentrations of outdoor fungi, and the daily levels of suspended PM (SPM) and PM ≤ 2.5 μm (PM_2.5). An increase in the interquartile range (46.2 CFU/m³) for outdoor fungal concentration led to PEF changes of −1.18 L/min (95% confidence interval, −2.27 to −0.08) in all children, 1.22 L/min (−2.96 to 5.41) in children without asthma, and −1.44 L/min (−2.57 to −0.32) in children with asthma. Outdoor fungi showed a significant negative correlation with PM_2.5 levels (r = −0.4, p = 0.04), but not with SPM (r = ‒0.3, p = 0.10) levels. Outdoor fungi may be associated with pulmonary dysfunction in children. Furthermore, children with asthma may show greater pulmonary dysfunction than those without asthma. Full article

Open AccessArticle The Chinese Herbal Medicine Formula mKG Suppresses Pulmonary Fibrosis of Mice Induced by Bleomycin

by Ying Gao, Li-Fu Yao, Yang Zhao, Li-Man Wei, Peng Guo, Meng Yu, Bo Cao, Tan Li, Hong Chen and Zhong-Mei Zou

Int. J. Mol. Sci. 2016, 17(2), 238; doi:10.3390/ijms17020238

Received: 6 January 2016 / Revised: 3 February 2016 / Accepted: 4 February 2016 / Published: 15 February 2016

Abstract

Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal

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Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicine, has a prominent anti-inflammatory effect. The present study is to explore the inhibitory effects of mKG on bleomycin (BLM)-induced pulmonary fibrosis in mice. mKG significantly decreased pulmonary alveolitis, fibrosis scores, and interleukin-6 (IL-6), interleukin-17 (IL-17), transforming growth factor-β (TGF-β) and hydroxyproline (HYP) levels in lung tissue of mice compared with BLM treatment. It markedly alleviated the increase of HYP content in the lung tissues and pathologic changes of pulmonary fibrosis caused by BLM instillation. In conclusion, mKG has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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Open AccessReview Exogenous Glutamine in Respiratory Diseases: Myth or Reality?

by Gisele P. Oliveira, Marcelo Gama de Abreu, Paolo Pelosi and Patricia R. M. Rocco

Nutrients 2016, 8(2), 76; doi:10.3390/nu8020076

Received: 30 November 2015 / Revised: 20 January 2016 / Accepted: 26 January 2016 / Published: 4 February 2016

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Abstract

Several respiratory diseases feature increased inflammatory response and catabolic activity, which are associated with glutamine depletion; thus, the benefits of exogenous glutamine administration have been evaluated in clinical trials and models of different respiratory diseases. Recent reviews and meta-analyses have focused on the

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Several respiratory diseases feature increased inflammatory response and catabolic activity, which are associated with glutamine depletion; thus, the benefits of exogenous glutamine administration have been evaluated in clinical trials and models of different respiratory diseases. Recent reviews and meta-analyses have focused on the effects and mechanisms of action of glutamine in a general population of critical care patients or in different models of injury. However, little information is available about the role of glutamine in respiratory diseases. The aim of the present review is to discuss the evidence of glutamine depletion in cystic fibrosis (CF), asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and lung cancer, as well as the results of exogenous glutamine administration in experimental and clinical studies. Exogenous glutamine administration might be beneficial in ARDS, asthma, and during lung cancer treatment, thus representing a potential therapeutic tool in these conditions. Further experimental and large randomized clinical trials focusing on the development and progression of respiratory diseases are necessary to elucidate the effects and possible therapeutic role of glutamine in this setting. Full article

Open AccessArticle The Effects of Vitamin D Supplementation on Pulmonary Function of Chronic Obstructive Pulmonary Disease Patients, before and after Clinical Trial

by Seyed Ali Javad Moosavi and Maryam Haddadzadeh Shoushtari

Diseases 2015, 3(4), 253-259; doi:10.3390/diseases3040253

Received: 3 July 2015 / Accepted: 8 October 2015 / Published: 16 October 2015

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Abstract

Vitamin D has several extra calcemic effects. Vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients but little is known about it’s association with lung function. Objective: To investigate whether supplementation with vitamin D could improve pulmonary function in

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Vitamin D has several extra calcemic effects. Vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients but little is known about it’s association with lung function. Objective: To investigate whether supplementation with vitamin D could improve pulmonary function in COPD patients. Design: Before and after, double center, clinical trial. Setting: Hazrat Rasoul University Hospital, Tehran, and Imam Khomaini University Hospital, Ahvaz, Iran. Participants: 24 patients with mild to very severe COPD. Intervention: Loading dose of 300,000–600,000 International Units (IU) of vitamin D, then 50000 IU weekly for 12 weeks. Measurements: The outcomes included forced expiratory volume in one second (FEV1), forced vital capacity (FVC), vital capacity (VC), forced expiratory flow between 25%–75% of forced vital capacity (FEF 25%–75%), exercise capacity according to the six minute walk test(6MWT) and the saturation of oxygen during exercise. Results: The mean FEV1 (p-value = 0.866), FVC (p-value = 0.475) and VC (p-value = 0.425) were not significantly different before and after intervention. FEF 25%–75% did not improve with this intervention (p-value = 0.555). The vitamin D supplementation did not have any significant effect on the exercise capacity (p-value=0.175) or the saturation of oxygen (p-value = 0.635). Conclusion: Pulmonary function and exercise capacity did not improve with vitamin D supplementation in COPD patients. Full article

Open AccessArticle Mosaic Pattern of Lung Attenuation on Chest CT in Patients with Pulmonary Hypertension

by Kamonpun Ussavarungsi, Augustine S. Lee and Charles D. Burger

Diseases 2015, 3(3), 205-212; doi:10.3390/diseases3030205

Received: 10 July 2015 / Revised: 21 August 2015 / Accepted: 2 September 2015 / Published: 7 September 2015

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Abstract

A mosaic pattern of lung attenuation on chest computed tomography (CT) may be due to various etiologies. There is limited published data on CT results when used to evaluate pulmonary hypertension (PH). We retrospectively studied the frequency of mosaic pattern in patients with

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A mosaic pattern of lung attenuation on chest computed tomography (CT) may be due to various etiologies. There is limited published data on CT results when used to evaluate pulmonary hypertension (PH). We retrospectively studied the frequency of mosaic pattern in patients with PH and the cause of the PH by diagnostic group, as well as the correlation between the mosaic pattern and the following: demographics, severity of the PH, main pulmonary artery (PA) size, PA/aorta (PA/Ao) ratio, pulmonary function tests (PFT), and ventilation perfusion scan results. Overall, 18% of the cohort had CT mosaic pattern (34/189). Mosaic pattern was present in 17/113 (15%) in Group 1 pulmonary arterial hypertension, 5/13 (28%) in Group 2 pulmonary venous hypertension and 8/50 (16%) in Group 3 PH. Conversely, Group 4 chronic thromboembolic PH was more prevalent in 4/8 (50%). Main PA size, PA/Ao ratio, and segmental perfusion defect were positively associated with mosaic pattern. In contrast, factors such as age, gender, body mass index, functional class, hemodynamic data, and PFT values were not associated with mosaic pattern. Mosaic pattern is not specific as an isolated finding for distinguishing the subtype of PH. Full article

Open AccessReview The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

by Seok-Jo Kim, Paul Cheresh, Renea P. Jablonski, David B. Williams and David W. Kamp

Int. J. Mol. Sci. 2015, 16(9), 21486-21519; doi:10.3390/ijms160921486

Received: 20 June 2015 / Revised: 29 July 2015 / Accepted: 26 August 2015 / Published: 7 September 2015

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Abstract

Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure).

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Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases) Printed Edition available

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Open AccessArticle Prevalence of Sodium and Fluid Restriction Recommendations for Patients with Pulmonary Hypertension

by Tonya Zeiger, Giovanna Cueva Cobo, Christine Dillingham and Charles D. Burger

Healthcare 2015, 3(3), 630-636; doi:10.3390/healthcare3030630

Received: 12 April 2015 / Revised: 16 July 2015 / Accepted: 21 July 2015 / Published: 28 July 2015

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Abstract

Background: Patients with pulmonary hypertension (PH) are often afflicted with the consequences of right heart failure including volume overload. Counseling to assist the patient in the dietary restriction of sodium and fluid may be underutilized. Methods: Consecutive patients seen in the

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Background: Patients with pulmonary hypertension (PH) are often afflicted with the consequences of right heart failure including volume overload. Counseling to assist the patient in the dietary restriction of sodium and fluid may be underutilized. Methods: Consecutive patients seen in the PH Clinic at Mayo Clinic in Florida from June to November 2013. Results: 100 patients were included; 70 were women and most had group 1 PH (n = 69). Patient characteristics using mean (±SD) were: Age 63 ± 13 years, functional class 3 ± 1, brain natriuretic peptide 302 ± 696 pg/mL, 6-min walk 337 ± 116 m, right atrial pressure 8 ± 5 mmHg, and mean pulmonary artery pressure 42 ± 13 mmHg. Overall, 79 had had complete (32) or partial instruction (47) and 21 had no prior counseling to restrict sodium or fluid. Of the 47 with partial instruction, 42 received complete education during the PH Clinic visit. Of the 21 without prior instruction, 19 received complete education during the PH visit. Seven patients with the opportunity to have their education enhanced or provided did not receive any additional counseling during the PH visit. Conclusion: Sodium and fluid restriction is an important but perhaps underutilized strategy to manage volume overload in patients with right heart failure. Focused questioning and education may permit an increase in the patients receiving instruction in this regard. Full article

Open AccessArticle Effect of Naturally Occurring Ozone Air Pollution Episodes on Pulmonary Oxidative Stress and Inflammation

by Cheryl Pirozzi, Anne Sturrock, Hsin-Yi Weng, Tom Greene, Mary Beth Scholand, Richard Kanner and Robert Paine III

Int. J. Environ. Res. Public Health 2015, 12(5), 5061-5075; doi:10.3390/ijerph120505061

Received: 19 March 2015 / Revised: 6 May 2015 / Accepted: 7 May 2015 / Published: 12 May 2015

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Abstract

This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with

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This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with chronic obstructive pulmonary disease (COPD) compared to controls. We measured biomarkers (nitrite/nitrate (NO_x), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms in 11 former smokers with moderate-to-severe COPD and nine former smokers without airflow obstruction during periods of low and high ozone air pollution. High ozone levels were associated with increased NO_x in EBC in both COPD (8.7 (±8.5) vs. 28.6 (±17.6) μmol/L on clean air vs. pollution days, respectively, p < 0.01) and control participants (7.6 (±16.5) vs. 28.5 (±15.6) μmol/L on clean air vs. pollution days, respectively, p = 0.02). There was no difference in pollution effect between COPD and control groups, and no difference in EBC 8-isoprostane, pulmonary function, or respiratory symptoms between clean air and pollution days in either group. Former smokers both with and without airflow obstruction developed airway oxidative stress and inflammation in association with ozone air pollution episodes. Full article

Open AccessArticle Prognostication in Pulmonary Arterial Hypertension with Submaximal Exercise Testing

by Vinod Khatri, Jennifer E. Neal, Charles D. Burger and Augustine S. Lee

Diseases 2015, 3(1), 15-23; doi:10.3390/diseases3010015

Received: 11 December 2014 / Revised: 26 December 2014 / Accepted: 27 January 2015 / Published: 6 February 2015

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Abstract

Introduction: The submaximal exercise test (SET), which gives both a measure of exercise tolerance, as well as disease severity, should be a more robust functional and prognostic marker than the six-minute walk test (6MWT). This study aimed to determine the prognostic value of

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Introduction: The submaximal exercise test (SET), which gives both a measure of exercise tolerance, as well as disease severity, should be a more robust functional and prognostic marker than the six-minute walk test (6MWT). This study aimed to determine the prognostic value of SET as predicted by the validated REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Artery Hypertension Disease Management) registry risk score (RRRS). Methods: Sixty-five consecutive patients with idiopathic and associated pulmonary arterial hypertension (PAH) underwent right-heart catheterization, echocardiogram, 6MWT and a three-minute SET (Shape-HF™). Analyses explored the association between SET variables and prognosis predicted by the RRRS. Results: Although multiple SET variables correlated with the RRRS on univariate analyses, only V_E/V_CO2 (r = 0.57, p < 0.0001) remained an independent predictor in multivariate analysis (β = 0.05, p = 0.0371). Additionally, the V_E/V_CO2 was the most discriminatory (area under receiver operating characteristic curve, 0.84) in identifying the highest-risk category (RRRS ≥ 10), with an optimal cut-off of 40.6, resulting in a high sensitivity (92%) and negative-predictive value (97%), but a lower specificity (67%). Conclusion: SETs, particularly the V_E/V_CO2, appear to have prognostic value when compared to the RRRS. If validated in prospective trials, SET should prove superior to the 6MWT or the RRRS, with significant implications for both future clinical trials and clinical practice. Full article

Open AccessReview Right or Left: The Role of Nanoparticles in Pulmonary Diseases

by Xuefei Lu, Tao Zhu, Chunying Chen and Ying Liu

Int. J. Mol. Sci. 2014, 15(10), 17577-17600; doi:10.3390/ijms151017577

Received: 21 February 2014 / Revised: 25 August 2014 / Accepted: 25 August 2014 / Published: 29 September 2014

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Abstract

Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring

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Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring to develop nanomaterials for improvement or replacement of traditional therapies. On the other hand, nanoparticles, as foreign material in human bodies, are reported to have potential adverse effects on the lung, including oxidase stress, inflammation, fibrosis and genotoxicity. Further, these damages could induce pulmonary diseases and even injuries in other tissues. It seems that nanoparticles may exert two-sided effects. Toxic effects of nanomaterials should be considered when their use is developed for therapies. Hence this review will attempt to summarize the two-side roles of nanoparticles in both therapies for pulmonary diseases and initiation of lung diseases and even secondary diseases caused by lung injuries. Determinants of these effects such as physicochemical properties of nanoparticles will also be discussed. Full article

(This article belongs to the Special Issue Nanotoxicology and Lung Diseases)

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Open AccessArticle TRAIL Deficient Mice Are Protected from Sugen/Hypoxia Induced Pulmonary Arterial Hypertension

by Sarah H. Dawson, Nadine D. Arnold, Josephine A. Pickworth, Sheila E. Francis and Allan Lawrie

Diseases 2014, 2(3), 260-273; doi:10.3390/diseases2030260

Received: 11 March 2014 / Revised: 15 July 2014 / Accepted: 28 July 2014 / Published: 31 July 2014

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Abstract

Pulmonary arterial hypertension (PAH) is a progressive lung disease diagnosed by an increase in pulmonary arterial blood pressure that is driven by a progressive vascular remodelling of small pulmonary arterioles. We have previously reported that tumor necrosis factor apoptosis-inducing ligand (TRAIL) protein expression

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Pulmonary arterial hypertension (PAH) is a progressive lung disease diagnosed by an increase in pulmonary arterial blood pressure that is driven by a progressive vascular remodelling of small pulmonary arterioles. We have previously reported that tumor necrosis factor apoptosis-inducing ligand (TRAIL) protein expression is increased in pulmonary vascular lesions and pulmonary artery smooth muscle cells (PASMC) of patients with idiopathic PAH. The addition of recombinant TRAIL induces the proliferation and migration of PASMCs in vitro. TRAIL is required for hypoxia-induced pulmonary hypertension in mice, and blockade of TRAIL prevents and reduces disease development in other rodent models of PAH. Due to the availability of knockout and transgenic mice, murine models of disease are key to further advances in understanding the complex and heterogeneous pathogenesis of PAH. However, murine models vary in their disease severity, and are often criticized for lacking the proliferative pulmonary vascular lesions characteristic of PAH. The murine Sugen-hypoxic (SuHx) mouse model has recently been reported to have a more severe PAH phenotype consisting advanced pulmonary vascular remodelling. We therefore aimed to determine whether TRAIL was also required for the development of PAH in this model. C57BL/6 and TRAIL^−/− mice were exposed to normoxia, Sugen5416 alone, hypoxia or both Sugen5416 and hypoxia (SuHx). We report here that SuHx treated C57BL/6 mice developed more severe PAH than hypoxia alone, and that TRAIL^−/− mice were protected from disease development. These data further emphasise the importance of this pathway and support the use of the SuHx mouse model for investigating the importance of potential mediators in PAH pathogenesis. Full article

(This article belongs to the Special Issue Pulmonary Arterial Hypertension (PAH))

Open AccessReview The Significance of Pulmonary Artery Size in Pulmonary Hypertension

by Kamonpun Ussavarungsi, Joseph P. Whitlock, Taylor A. Lundy, Ivan D. Carabenciov, Charles D. Burger and Augustine S. Lee

Diseases 2014, 2(3), 243-259; doi:10.3390/diseases2030243

Received: 12 June 2014 / Revised: 21 July 2014 / Accepted: 25 July 2014 / Published: 31 July 2014

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Abstract

Pulmonary hypertension (PH) has been found to have significant morbidity and mortality. The treatment of PH has advanced considerably with increasingly more effective and safer options. With an increasing effort to diagnose patients early, non-invasive techniques are often used to screen those patients

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Pulmonary hypertension (PH) has been found to have significant morbidity and mortality. The treatment of PH has advanced considerably with increasingly more effective and safer options. With an increasing effort to diagnose patients early, non-invasive techniques are often used to screen those patients likely to have PH. Computerized tomography (CT) chest scans are increasingly utilized in the evaluation of patients with exertional dyspnea, including those with suspected PH. The main role of the CT scan is to evaluate for any associated underlying diseases. There have been attempts to address the utility of CT to predict the presence of PH. This article reviews previously published investigations to summarize the relationship between pulmonary artery dimensions and PH to determine both the strength of the correlation and its discriminatory ability for use in clinical practice. Full article

(This article belongs to the Special Issue Pulmonary Arterial Hypertension (PAH))

Open AccessArticle Dehydroabietic Acid Isolated from Commiphora opobalsamum Causes Endothelium-Dependent Relaxation of Pulmonary Artery via PI3K/Akt-eNOS Signaling Pathway

by Wenyan Gao, Xiaoyan Dong, Nan Xie, Chunlan Zhou, Yuhua Fan, Guoyou Chen, Yanming Wang, Taiming Wei and Daling Zhu

Molecules 2014, 19(6), 8503-8517; doi:10.3390/molecules19068503

Received: 12 March 2014 / Revised: 16 June 2014 / Accepted: 17 June 2014 / Published: 23 June 2014

Cited by 5 | Viewed by 1610 | PDF Full-text (1229 KB) | HTML Full-text | XML Full-text

Abstract

Commiphora opobalsamum is a Traditional Chinese Medicine used to treat traumatic injury, mainly by relaxing blood vessels. In this study, two diterpenes, dehydroabietic acid (DA) and sandaracopimaric acid (SA) were obtained from it by a bioassay-guided approach using isolated

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Commiphora opobalsamum is a Traditional Chinese Medicine used to treat traumatic injury, mainly by relaxing blood vessels. In this study, two diterpenes, dehydroabietic acid (DA) and sandaracopimaric acid (SA) were obtained from it by a bioassay-guided approach using isolated rat pulmonary artery rings. The structures of the two compounds were elucidated by spectroscopic methods (IR, ¹H- and ¹³C-NMR, HR-ESI-MS). Both DA and SA reduced the contraction of phenylephrine-induced pulmonary arteries in a concentration-dependent manner, and endothelium contributed greatly to the vasodilatory effect of DA. This effect of DA was attenuated by N^G-Nitro-L-arginine methyl ester (L-NAME, an eNOS inhibitor). Meanwhile, DA increased nitric oxide (NO) production, along with the increase of phosphorylation level of eNOS and Akt in endothelial cells. LY294002 (a PI3K inhibitor) could reverse this effect, which suggested the endothelial PI3K/Akt pathway involved in the mechanism underlying DA-induced relaxation of pulmonary artery. This work provided evidence of vasorelaxant substances in Commiphora opobalsamum and validated that PI3K/Akt-eNOS pathway was associated with DA-induced pulmonary artery vasodilation. Full article

(This article belongs to the Section Natural Products)

► Figures

Open AccessArticle The Cross Talk between cGMP Signal Pathway and PKC in Pulmonary Endothelial Cell Angiogenesis

by Zhen Zeng, Ying-Chuan Li, Zhi-Hua Jiao, Jun Yao and Ying Xue

Int. J. Mol. Sci. 2014, 15(6), 10185-10198; doi:10.3390/ijms150610185

Received: 15 April 2014 / Revised: 4 May 2014 / Accepted: 14 May 2014 / Published: 6 June 2014

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Abstract

Angiogenic proliferation of vascular endothelial cells is believed to play an important role in pulmonary vascular remodeling in pulmonary arterial hypertension. In the present study, we found that c-GMP (cyclic guanosine monophosphate) inhibited the proliferation and tube formation of pulmonary vascular endothelial cells

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Angiogenic proliferation of vascular endothelial cells is believed to play an important role in pulmonary vascular remodeling in pulmonary arterial hypertension. In the present study, we found that c-GMP (cyclic guanosine monophosphate) inhibited the proliferation and tube formation of pulmonary vascular endothelial cells induced by TGF-β1, and that this process was reversed by PKG (protein kinase G) inhibitor and PKC (protein kinase C) inhibitor. In addition, small interfering RNA (siRNA) targeting ERK also reduced cellular proliferation. Furthermore, western blotting showed that cGMP down-regulated the phosphorylation level of ERK1/2, which was reversed not only by PKG inhibitor but also by PKC inhibitor. Silencing different PKC isoforms showed that PKCΔ, PKCγ and PKCα were involved in ERK phosphorylation, suggesting that PKC kinases have a permissive action. Three subtypes, PKCΔ, PKCγ and PKCα are likely to be involved the phosphorylation suppression of ERK included cGMP. Taken together, these data suggest that ERK phosphorylation mediates the proliferation of pulmonary vascular endothelial cells, and PKC kinases have a permissive action in this process. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension

by Megha Talati, Haitham Mutlak, Kirk B. Lane, Wei Han, Anna Hemnes, Outi Mutlak, Tom Blackwell, Rinat Zaynagetdinov, Timothy S. Blackwell and James West

Diseases 2014, 2(2), 148-167; doi:10.3390/diseases2020148

Received: 18 April 2014 / Revised: 20 May 2014 / Accepted: 21 May 2014 / Published: 30 May 2014

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Abstract

Aim: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2^R899X mouse

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Aim: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2^R899X mouse lung and immunohistochemistry for NF-κB p65 in human PAH lung demonstrate that NF-κB is activated in end-stage disease. Acute inflammation or expression of a constitutively active NF-κB elicits a strong suppression of the BMP pathway in mice inversely correlating to activation of NF-κB targets. However, Bmpr2 mutation does not result in NF-κB activation in early disease development as assessed by luciferase reporter mice. Moreover, Bmpr2 mutant mice in which NF-κB activation is genetically blocked develop PH indistinguishable from that without the block. Finally, delivery of a virus causing NF-κB activation strongly exacerbates development of PH in Bmpr2 mutant mice, associated with increased remodeling. Conclusion: NF-κB activation exacerbates, but is not required for Bmpr2-related PH. Pulmonary vascular-specific activation of NF-κB may be a “second hit” that drives penetrance in heritable PH. Full article

(This article belongs to the Special Issue Pulmonary Arterial Hypertension (PAH))

Open AccessReview The Role of Exercise Testing in the Modern Management of Pulmonary Arterial Hypertension

by Martin K. Johnson and Stephen Thomson

Diseases 2014, 2(2), 120-147; doi:10.3390/diseases2020120

Received: 12 April 2014 / Revised: 28 April 2014 / Accepted: 30 April 2014 / Published: 28 May 2014

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Abstract

A culture of exercise testing is firmly embedded in the management of pulmonary arterial hypertension (PAH) but its clinical relevance and utility have recently been under some debate. The six minute walk test (6MWT) has been used as a primary outcome measure to

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A culture of exercise testing is firmly embedded in the management of pulmonary arterial hypertension (PAH) but its clinical relevance and utility have recently been under some debate. The six minute walk test (6MWT) has been used as a primary outcome measure to enable the licensing of many of the medications used for this condition. Recent reviews have questioned the validity of this test as a surrogate of clinical outcomes. At the same time, other questions are emerging where exercise testing may be the solution. With the rise in understanding of genetic markers of idiopathic PAH (IPAH), the screening of an otherwise healthy population for incipient pulmonary hypertension (PH) will be required. The proliferation in treatment choices and identification of populations with PH where PAH treatment is not indicated, such as left heart and lung disease, requires more definitive differentiation from patients with PAH. There is a continuing question about the existence and clinical relevance of exercise induced PAH as a cause of unexplained dyspnoea and fatigue and as a latent phase of resting PH. This review presents a summary and critical analysis of the current role of exercise testing in PAH and speculates on future trends. Full article

(This article belongs to the Special Issue Pulmonary Arterial Hypertension (PAH))

Open AccessArticle Baicalin Inhibits Hypoxia-Induced Pulmonary Artery Smooth Muscle Cell Proliferation via the AKT/HIF-1α/p27-Associated Pathway

by Lin Zhang, Zhichen Pu, Junsong Wang, Zhifeng Zhang, Dongmei Hu and Junjie Wang

Int. J. Mol. Sci. 2014, 15(5), 8153-8168; doi:10.3390/ijms15058153

Received: 25 March 2014 / Revised: 27 April 2014 / Accepted: 30 April 2014 / Published: 9 May 2014

Cited by 11 | Viewed by 1713 | PDF Full-text (1059 KB) | HTML Full-text | XML Full-text

Abstract

Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has been shown to possess various pharmacological actions. Previous studies have revealed that baicalin inhibits the growth of cancer cells through the induction of apoptosis. Pulmonary arterial hypertension (PAH) is

[...] Read more.

Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has been shown to possess various pharmacological actions. Previous studies have revealed that baicalin inhibits the growth of cancer cells through the induction of apoptosis. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by enhanced pulmonary artery smooth muscle cell (PASMCs) proliferation and suppressed apoptosis. However, the potential mechanism of baicalin in the regulation of PASMC proliferation and the prevention of cardiovascular diseases remains unexplored. To test the effects of baicalin on hypoxia, we used rats treated with or without baicalin (100 mg·kg⁻¹ each rat) at the beginning of the third week after hypoxia. Hemodynamic and pulmonary pathomorphology data showed that right ventricular systolic pressures (RVSP), the weight of the right ventricle/left ventricle plus septum (RV/LV + S) ratio and the medial width of pulmonary arterioles were much higher in chronic hypoxia. However, baicalin treatment repressed the elevation of RVSP, RV/LV + S and attenuated the pulmonary vascular structure remodeling (PVSR) of pulmonary arterioles induced by chronic hypoxia. Additionally, baicalin (10 and 20 μmol·L⁻¹) treatment suppressed the proliferation of PASMCs and attenuated the expression of hypoxia-inducible factor-α (HIF-α) under hypoxia exposure. Meanwhile, baicalin reversed the hypoxia-induced reduction of p27 and increased AKT/protein kinase B phosphorylation p-AKT both in vivo and in vitro. These results suggested that baicalin could effectively attenuate PVSR and hypoxic pulmonary hypertension. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Microsomal Prostaglandin E Synthase-1 Deficiency Exacerbates Pulmonary Fibrosis Induced by Bleomycin in Mice

by Bo Wei, Linhong Cai, Dan Sun, Yanhua Wang, Cairui Wang, Xiaoyu Chai, Feng Xie, Ming Su, Fangrui Ding, Jie Liu, Jichun Yang, Youfei Guan and Xinmin Liu

Molecules 2014, 19(4), 4967-4985; doi:10.3390/molecules19044967

Received: 24 February 2014 / Revised: 8 April 2014 / Accepted: 11 April 2014 / Published: 21 April 2014

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Abstract

Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 (PGH₂) to prostaglandin E2 (PGE₂), plays an important role in a variety of diseases. So far, the role of mPGES-1 in idiopathic pulmonary fibrosis (IPF) remained unknown.

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Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 (PGH₂) to prostaglandin E2 (PGE₂), plays an important role in a variety of diseases. So far, the role of mPGES-1 in idiopathic pulmonary fibrosis (IPF) remained unknown. The current study aimed to investigate the role of mPGES-1 in pulmonary fibrosis induced by bleomycin in mice. We found that mPGES-1 deficient (mPGES-1⁻^/−) mice exhibited more severe fibrotic lesions with a decrease in PGE₂ content in lungs after bleomycin treatment when compared with wild type (mPGES-1^+/+) mice. The mPGES-1 expression levels and PGE₂ content were also decreased in bleomycin-treated mPGES-1^+/+ mice compared to saline-treated mPGES-1^+/+ mice. Moreover, in both mPGES-1⁻^/− and mPGES-1^+/+ mice, bleomycin treatment reduced the expression levels of E prostanoid receptor 2 (EP2) and EP4 receptor in lungs, whereas had little effect on EP1 and EP3. In cultured human lung fibroblast cells (MRC-5), siRNA-mediated knockdown of mPGES-1 augmented transforming growth factor-β1 (TGF-β1)-induced α-smooth muscle actin (α-SMA) protein expression, and the increase was reversed by treatment of PGE₂, selective EP2 agonist and focal adhesion kinase (FAK) inhibitor. In conclusion, these findings revealed mPGES-1 exerts an essential effect against pulmonary fibrogenesis via EP2-mediated signaling transduction, and activation of mPGES-1-PGE₂-EP2-FAK signaling pathway may represent a new therapeutic strategy for treatment of IPF patients. Full article

Open AccessArticle Atorvastatin Attenuates Bleomycin-Induced Pulmonary Fibrosis via Suppressing iNOS Expression and the CTGF (CCN2)/ERK Signaling Pathway

by Bo Zhu, Ai-Qun Ma, Lan Yang and Xiao-Min Dang

Int. J. Mol. Sci. 2013, 14(12), 24476-24491; doi:10.3390/ijms141224476

Received: 14 October 2013 / Revised: 28 November 2013 / Accepted: 3 December 2013 / Published: 16 December 2013

Cited by 18 | Viewed by 1890 | PDF Full-text (1935 KB) | HTML Full-text | XML Full-text

Abstract

Pulmonary fibrosis is a progressive and fatal lung disorder with high mortality rate. To date, despite the fact that extensive research trials are ongoing, pulmonary fibrosis continues to have a poor response to available medical therapy. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known for

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Pulmonary fibrosis is a progressive and fatal lung disorder with high mortality rate. To date, despite the fact that extensive research trials are ongoing, pulmonary fibrosis continues to have a poor response to available medical therapy. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known for its broad pharmacological activities, remains a remedy against multiple diseases. The present study investigated the antifibrotic potential of atorvastatin against bleomycin-induced lung fibrosis and to further explore the possible underlying mechanisms. Our results showed that atorvastatin administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. Atorvastatin reduced malondialdehyde (MDA) level and lung indices. Atorvastatin also markedly decreased the expression of inducible nitric oxide synthase (iNOS) in lung tissues and, thus, prevented nitric oxide (NO) release in response to bleomycin challenge. Furthermore, atorvastatin exhibited target down-regulation of connective tissue growth factor (CTGF (CCN2)) and phosphorylation extracellular regulated protein kinases (p-ERK) expression. Taken together, atorvastatin significantly ameliorated bleomycin-induced pulmonary fibrosis in rats, via the inhibition of iNOS expression and the CTGF (CCN2)/ERK signaling pathway. The present study provides evidence that atorvastatin may be a potential therapeutic reagent for the treatment of lung fibrosis. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

by Tao Zhu, Wei Zhang, Min Xiao, Hongying Chen and Hong Jin

Int. J. Mol. Sci. 2013, 14(12), 23581-23596; doi:10.3390/ijms141223581

Received: 9 October 2013 / Revised: 1 November 2013 / Accepted: 22 November 2013 / Published: 3 December 2013

Cited by 18 | Viewed by 1885 | PDF Full-text (2150 KB) | HTML Full-text | XML Full-text

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in

[...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF) were measured. HE staining and Masson’s trichrome (MT) staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA). On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Development and Evaluation of an Improved Technique for Pulmonary Function Testing Using Electrical Impedance Pneumography Intended for the Diagnosis of Chronic Obstructive Pulmonary Disease Patients

by Myeong Heon Sim, Min Yong Kim, In Cheol Jeong, Sung Bin Park, Suk Joong Yong, Won Ky Kim and Hyung Ro Yoon

Sensors 2013, 13(11), 15846-15860; doi:10.3390/s131115846

Received: 8 September 2013 / Revised: 22 October 2013 / Accepted: 12 November 2013 / Published: 21 November 2013

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Abstract

Spirometry is regarded as the only effective method for detecting pulmonary function test (PFT) indices. In this study, a novel impedance pulmonary function measurement system (IPFS) is developed for directly assessing PFT indices. IPFS can obtain high resolution values and remove motion artifacts

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Spirometry is regarded as the only effective method for detecting pulmonary function test (PFT) indices. In this study, a novel impedance pulmonary function measurement system (IPFS) is developed for directly assessing PFT indices. IPFS can obtain high resolution values and remove motion artifacts through real-time base impedance feedback. Feedback enables the detection of PFT indices using only both hands for convenience. IPFS showed no differences in the sitting, supine, and standing postures during the measurements, indicating that patient posture has no effect on IPFS. Mean distance analysis showed good agreement between the volume and flow signal of IPFS (p < 0.05). PFT indices were detected in subjects to differentiate a chronic obstructive pulmonary disease (COPD) patient group from a normal group. The forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁), FEV_1/FVC, and peak expiratory flow (PEF) in the COPD group were lower than those in the normal group by IPFS (p < 0.05). IPFS is therefore suitable for evaluating pulmonary function in normal and COPD patients. Moreover, IPFS could be useful for periodic monitoring of existing patients diagnosed with obstructive lung disease. Full article

(This article belongs to the Special Issue Biomedical Sensors and Systems)

Open AccessArticle Histone Deacetylase Inhibition Downregulates Collagen 3A1 in Fibrotic Lung Fibroblasts

by Xiangyu Zhang, Hui Liu, Thomas Hock, Victor J. Thannickal and Yan Y. Sanders

Int. J. Mol. Sci. 2013, 14(10), 19605-19617; doi:10.3390/ijms141019605

Received: 8 July 2013 / Revised: 27 August 2013 / Accepted: 11 September 2013 / Published: 27 September 2013

Cited by 16 | Viewed by 2131 | PDF Full-text (664 KB) | HTML Full-text | XML Full-text

Abstract

Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by chronic inflammation and excessive collagen accumulation in the lung. Myofibroblasts are the primary collagen-producing cells in pulmonary fibrosis. Histone deacetylase inhibitor (HDACi) can affect gene expression, and some, such as suberoylanilide hydroxamic acid

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Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by chronic inflammation and excessive collagen accumulation in the lung. Myofibroblasts are the primary collagen-producing cells in pulmonary fibrosis. Histone deacetylase inhibitor (HDACi) can affect gene expression, and some, such as suberoylanilide hydroxamic acid (SAHA), are US FDA approved for cancer treatment. In this study, we investigated SAHA’s effects on the expression of collagen III alpha 1 (COL3A1) in primary human IPF fibroblasts and in a murine model of pulmonary fibrosis. We observed that increased COL3A1 expression in IPF fibroblasts can be substantially reduced by SAHA treatment at the level of transcription as detected by RT-PCR; collagen III protein level was also reduced, as detected by Western blots and immunofluorescence. The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells. Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac. In our murine model of bleomycin-induced pulmonary fibrosis, the SAHA treated group demonstrated significantly less collagen III, as detected by immunohistochemistry. Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Metabolic Profiling of Plasma from Benign and Malignant Pulmonary Nodules Patients Using Mass Spectrometry-Based Metabolomics

by Liang Gao, Zongmei Wen, Chunyan Wu, Tao Wen and Choon Nam Ong

Metabolites 2013, 3(3), 539-551; doi:10.3390/metabo3030539

Received: 3 May 2013 / Revised: 7 June 2013 / Accepted: 24 June 2013 / Published: 4 July 2013

Abstract

Solitary pulmonary nodule (SPN or coin lesion) is a mass in the lung and can be commonly found in chest X-rays or computerized tomography (CT) scans. However, despite the advancement of imaging technologies, it is still difficult to distinguish malignant cancer from benign

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Solitary pulmonary nodule (SPN or coin lesion) is a mass in the lung and can be commonly found in chest X-rays or computerized tomography (CT) scans. However, despite the advancement of imaging technologies, it is still difficult to distinguish malignant cancer from benign SPNs. Here we investigated the metabolic profiling of patients with benign and malignant pulmonary nodules. A combination of gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) was used to profile the plasma metabolites in 17 patients with malignant SPNs, 15 patients with benign SPNs and 20 healthy controls. The metabolic profiles were assayed using OPLS-DA, and further analyzed to identify marker metabolites related to diseases. Both GC/MS- and LC/MS-derived models showed clear discriminations in metabolic profiles among three groups. It was found that 63 metabolites (12 from GC/MS, 51 from LC/MS) contributed to the differences. Of these, 48 metabolites showed same change trend in both malignant and benign SPNs as compared with healthy controls, indicating some common pathways including inflammation and oxidative injury shared by two diseases. In contrast, 14 metabolites constituted distinct profiles that differentiated malignant from benign SPNs, which might be a unique biochemical feature associated with lung cancer. Overall, our data suggested that integration of two highly sensitive and complementary metabolomics platforms could enable a comprehensive metabolic profiling and assist in discrimination malignant from benign SPNs. Full article

(This article belongs to the Special Issue Cancer Metabolomics)

Open AccessArticle Cyclic Stretch Induces Inducible Nitric Oxide Synthase and Soluble Guanylate Cyclase in Pulmonary Artery Smooth Muscle Cells

by Monica R. Shah, Stephen Wedgwood, Lyubov Czech, Gina A. Kim, Satyan Lakshminrusimha, Paul T. Schumacker, Robin H. Steinhorn and Kathryn N. Farrow

Int. J. Mol. Sci. 2013, 14(2), 4334-4348; doi:10.3390/ijms14024334

Received: 31 December 2012 / Revised: 12 February 2013 / Accepted: 17 February 2013 / Published: 21 February 2013

Cited by 8 | Viewed by 2035 | PDF Full-text (581 KB) | HTML Full-text | XML Full-text

Abstract

In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling. Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation. Pulmonary artery smooth muscle cells (PASMCs) express inducible

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In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling. Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation. Pulmonary artery smooth muscle cells (PASMCs) express inducible nitric oxide synthase (iNOS), and while iNOS expression increases during late gestation, little is known about how cyclic stretch impacts this pathway. In this study, PASMC were subjected to cyclic stretch of 20% amplitude and frequency of 1 Hz for 24 h and compared to control cells maintained under static conditions. Cyclic stretch significantly increased cytosolic oxidative stress as compared to static cells (62.9 ± 5.9% vs. 33.3 ± 5.7% maximal oxidation), as measured by the intracellular redox sensor roGFP. Cyclic stretch also increased sGCβ protein expression (2.5 ± 0.9-fold), sGC activity (1.5 ± 0.2-fold) and cGMP levels (1.8 ± 0.2-fold), as well as iNOS mRNA and protein expression (3.0 ± 0.9 and 2.6 ± 0.7-fold, respectively) relative to control cells. An antioxidant, recombinant human superoxide dismutase (rhSOD), significantly decreased stretch-induced cytosolic oxidative stress, but did not block stretch-induced sGC activity. Inhibition of iNOS with 1400 W or an iNOS-specific siRNA inhibited stretch-induced sGC activity by 30% and 68% respectively vs. static controls. In conclusion, cyclic stretch increases sGC expression and activity in an iNOS-dependent manner in PASMC from fetal lambs. The mechanism that produces iNOS and sGC upregulation is not yet known, but we speculate these effects represent an early compensatory mechanism to counteract the effects of stretch-induced oxidative stress. A better understanding of the interplay between these two distinct pathways could provide key insights into future avenues to treat infants with pulmonary hypertension. Full article

(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)

Open AccessArticle Role of Carnitine Acetyl Transferase in Regulation of Nitric Oxide Signaling in Pulmonary Arterial Endothelial Cells

by Shruti Sharma, Xutong Sun, Saurabh Agarwal, Ruslan Rafikov, Sridevi Dasarathy, Sanjiv Kumar and Stephen M. Black

Int. J. Mol. Sci. 2013, 14(1), 255-272; doi:10.3390/ijms14010255

Received: 16 October 2012 / Revised: 26 November 2012 / Accepted: 30 November 2012 / Published: 21 December 2012

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Abstract

Congenital heart defects with increased pulmonary blood flow (PBF) result in pulmonary endothelial dysfunction that is dependent, at least in part, on decreases in nitric oxide (NO) signaling. Utilizing a lamb model with left-to-right shunting of blood and increased PBF that mimics the

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Congenital heart defects with increased pulmonary blood flow (PBF) result in pulmonary endothelial dysfunction that is dependent, at least in part, on decreases in nitric oxide (NO) signaling. Utilizing a lamb model with left-to-right shunting of blood and increased PBF that mimics the human disease, we have recently shown that a disruption in carnitine homeostasis, due to a decreased carnitine acetyl transferase (CrAT) activity, correlates with decreased bioavailable NO. Thus, we undertook this study to test the hypothesis that the CrAT enzyme plays a major role in regulating NO signaling through its effect on mitochondrial function. We utilized the siRNA gene knockdown approach to mimic the effect of decreased CrAT activity in pulmonary arterial endothelial cells (PAEC). Our data indicate that silencing the CrAT gene disrupted cellular carnitine homeostasis, reduced the expression of mitochondrial superoxide dismutase-and resulted in an increase in oxidative stress within the mitochondrion. CrAT gene silencing also disrupted mitochondrial bioenergetics resulting in reduced ATP generation and decreased NO signaling secondary to a reduction in eNOS/Hsp90 interactions. Thus, this study links the disruption of carnitine homeostasis to the loss of NO signaling observed in children with CHD. Preserving carnitine homeostasis may have important clinical implications that warrant further investigation. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

Open AccessArticle Hydroxysafflor Yellow A (HSYA) from Flowers of Carthamus tinctorius L. and Its Vasodilatation Effects on Pulmonary Artery

by Yuhua Bai, Ping Lu, Chenghua Han, Chunyue Yu, Minggang Chen, Fa He, Dan Yi and Lijun Wu

Molecules 2012, 17(12), 14918-14927; doi:10.3390/molecules171214918

Received: 22 October 2012 / Revised: 19 November 2012 / Accepted: 7 December 2012 / Published: 13 December 2012

Cited by 9 | Viewed by 2240 | PDF Full-text (368 KB)

Abstract

Flowers of Carthamus tinctorius L. are traditionally used in China to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of Carthamus tinctorius L. flowers, is known for its multiple biological activities. In the present study, HSYA was isolated from

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Flowers of Carthamus tinctorius L. are traditionally used in China to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of Carthamus tinctorius L. flowers, is known for its multiple biological activities. In the present study, HSYA was isolated from Carthamus tinctorius L. flowers by a macroporous resin adsorption chromatography method coupled with a Waters high-throughput auto-purification system and it's vasodilatation effects on pulmonary artery (PA) were explored by an assay of tension study on rat pulmonary artery (PA) rings. Results suggest that HSYA possesses vascular relaxation effects on rat PA by activating the KV channel in pulmonary vascular smooth muscle cells (PVSMCs). Full article

(This article belongs to the Section Natural Products)

Open AccessArticle Fasudil, a Rho-Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

by Chunguo Jiang, Hui Huang, Jia Liu, Yanxun Wang, Zhiwei Lu and Zuojun Xu

Int. J. Mol. Sci. 2012, 13(7), 8293-8307; doi:10.3390/ijms13078293

Received: 21 May 2012 / Revised: 19 June 2012 / Accepted: 28 June 2012 / Published: 4 July 2012

Cited by 33 | Viewed by 2606 | PDF Full-text (2727 KB) | HTML Full-text | XML Full-text

Abstract

The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF) involve multiple pathways, such as inﬂammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK), may interact with other signaling pathways known to

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The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF) involve multiple pathways, such as inﬂammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK), may interact with other signaling pathways known to contribute to pulmonary ﬁbrosis. This study aimed to determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice. Our results showed that the Aschcroft score and hydroxyproline content of the bleomycin-treated mouse lung decreased in response to fasudil treatment. The number of infiltrated inflammatory cells in the bronchoalveolar lavage fluid (BALF) was attenuated by fasudil. In addition, fasudil reduced the production of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein expression in bleomycin-induced pulmonary fibrosis. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary ﬁbrosis. Full article

Open AccessArticle Polydatin Attenuates Hypoxic Pulmonary Hypertension and Reverses Remodeling through Protein Kinase C Mechanisms

by Qing Miao, Xiao-Peng Shi, Ming-Xiang Ye, Jin Zhang, Shan Miao, Si-Wang Wang, Bo Li, Xiu-Xiu Jiang, Song Zhang, Nan Hu, Juan Li and Jian Zhang

Int. J. Mol. Sci. 2012, 13(6), 7776-7787; doi:10.3390/ijms13067776

Received: 10 April 2012 / Revised: 11 May 2012 / Accepted: 12 June 2012 / Published: 21 June 2012

Cited by 5 | Viewed by 2203 | PDF Full-text (447 KB) | HTML Full-text | XML Full-text

Abstract

Hypoxic pulmonary hypertension is a life-threatening emergency if untreated. Consistent pulmonary hypertension also leads to arteries and ventricular remodeling. The clinical therapeutic strategy for pulmonary hypertension and the corresponding remodeling mainly interacts with NO, angiotensin II (Ang II) and elevated endothelin (ET) targets.

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Hypoxic pulmonary hypertension is a life-threatening emergency if untreated. Consistent pulmonary hypertension also leads to arteries and ventricular remodeling. The clinical therapeutic strategy for pulmonary hypertension and the corresponding remodeling mainly interacts with NO, angiotensin II (Ang II) and elevated endothelin (ET) targets. In the present study, we evaluated the effects of polydatin on hypoxia-induced pulmonary hypertension. It was observed that polydatin attenuated hypoxic pulmonary hypertension, reversed remodeling, and regulated NO, Ang II, ET contents in the serum and lung samples. However, forced activation of PKC signaling by its selective activator thymeleatoxin (THX) could abate the effects of polydatain. These results suggest that polydatin might be a promising candidate for hypoxic pulmonary treatment through interaction with PKC mechanisms. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Cross-Sectional Analysis of the Utility of Pulmonary Function Tests in Predicting Emphysema in Ever-Smokers

by Sean E. Hesselbacher, Robert Ross, Matthew B. Schabath, E. O’Brian Smith, Sarah Perusich, Nadia Barrow, Pamela Smithwick, Manoj J. Mammen, Harvey Coxson, Natasha Krowchuk, David B. Corry and Farrah Kheradmand

Int. J. Environ. Res. Public Health 2011, 8(5), 1324-1340; doi:10.3390/ijerph8051324

Received: 15 January 2011 / Revised: 20 April 2011 / Accepted: 22 April 2011 / Published: 29 April 2011

Cited by 16 | Viewed by 3653 | PDF Full-text (640 KB) | HTML Full-text | XML Full-text

Abstract

Emphysema is largely an under-diagnosed medical condition that can exist in smokers in the absence of airway obstruction. We aimed to determine the sensitivity and specificity of pulmonary function tests (PFTs) in assessing emphysema using quantitative CT scans as the reference standard. We

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Emphysema is largely an under-diagnosed medical condition that can exist in smokers in the absence of airway obstruction. We aimed to determine the sensitivity and specificity of pulmonary function tests (PFTs) in assessing emphysema using quantitative CT scans as the reference standard. We enrolled 224 ever-smokers (current or former) over the age of 40. CT of thorax was used to quantify the low attenuation area (% emphysema), and to measure the standardized airway wall thickness. PFTs were used individually and in combination to predict their ability to discriminate radiographic emphysema. Significant emphysema (>7%) was detected in 122 (54%) subjects. Twenty six (21%) emphysema subjects had no evidence of airflow obstruction (FEV1/FVC ratio 23% emphysema showed airflow obstruction. The sensitivity and specificity of spirometry for detecting radiographic emphysema were 79% and 75%, respectively. Standardized airway wall thickness was increased in subjects with airflow obstruction, but did not correlate with emphysema severity. In this cohort of lifetime ever-smokers, PFTs alone were inadequate for diagnosing emphysema. Airway wall thickness quantified by CT morphometry was associated with airflow limitation, but not with emphysema indicating that the heterogeneous nature of lung disease in smokers may represent distinct phenotypes. Full article

(This article belongs to the Special Issue Tobacco Smoking and Public Health)

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