Search Results (107)

Acute respiratory distress syndrome (ARDS) causes heterogeneous injury, with normal, unstable, and edematous tissue distributed throughout the lung. Although positive pressure ventilation initially reduced ARDS-related mortality, it became clear that the ventilator can be a double-edged sword and, if set improperly, can worsen outcomes. This uneven pathology makes the lung vulnerable to secondary ventilator-induced lung injury (VILI). In 2000, evidence showed that lowering tidal volume (V_T) and airway pressure significantly reduced mortality in patients with ARDS, suggesting that this reduction led to less overdistension of healthy lung tissue. Including respiratory system compliance (C_RS) in the calculation. It was shown that low driving pressure (ΔP = V_T/C_RS) was more strongly associated with survival than low V_T alone. This idea was further extended into measuring the mechanical power delivered to the respiratory system: MP_rs = RR × ΔV²∙[1/2∙EL_rs + RR∙(1 + I:E)/60∙I:E∙R_aw] + ΔV∙PEEP, where EL_rs is elastance, I:E is inspiratory:expiratory ratio, R_aw is airway resistance, and RR is respiratory rate. This measure helps identify when the lung is at risk of VILI. However, a recent study found no direct causal link between MP_RS and mortality; rather, it showed that MP_RS, normalized to C_RS or end-expiratory lung volume (EELV), was independently associated with outcomes. This indicates that lung size and underlying pathophysiology—rather than ΔP or MP_RS alone—are critical determinants of VILI risk. Reopening collapsed lung tissue would increase C_RS and decrease E_RS, thereby lowering ΔP or MP_RS at any given V_T, R_aw, PEEP, I:E, or RR setting. Consequently, the focus should shift from simply adjusting the ventilator to normalize C_RS and EELV that reduce ΔP or MP_RS at higher ventilator settings. Full article

Background/Objectives: Preterm infants are at risk of developing the chronic lung condition of bronchopulmonary dysplasia (BPD), with associated alveolar simplification and airway hyperreactivity. Inhibition of S-nitrosoglutathione (GSNO) reductase has been shown to rescue airway hyperreactivity in a murine model of BPD. Here, we investigate the effects of early treatment with N6022, a pharmacologic GSNO reductase inhibitor. Methods: Newborn C57BL/6 mice were exposed to either 21% (control) or 60% oxygen (BPD model) for 5 days after birth. Pups simultaneously received either subcutaneous saline or varying doses of N6022 for 5 days during hyperoxia exposure. Pups were then recovered in room air to 3 weeks postnatal age. H&E-stained lungs were analyzed for alveolar simplification and airway tethering. In vivo airway reactivity to inhaled methacholine was measured using a flexiVent system. In separate littermates, lungs were immediately harvested after 5 days of hyperoxia for protein quantification via automated capillary Westerns. Results: Alveolar simplification and decreased airway tethering were noted in the 60% + saline group. Pups treated with N6022 during hyperoxia displayed dose-dependent improvements in alveolar simplification and airway tethering. Similarly, hyperoxia-exposed pups had increased airway reactivity, as measured by elevated respiratory system resistance and elastance responses to methacholine. Treatment with 10 mg/kg/day N6022 during hyperoxia resulted in decreased resistance and elastance responses. TGF-β expressions were elevated in the 60% + saline group and attenuated in the 60% + N6022 groups. Conclusions: Early exposure to GSNO reductase inhibitors such as N6022 can prevent hyperoxia-induced alveolar simplification and airway hyperreactivity, with lasting effects even after cessation of treatment. Full article

Early-life respiratory syncytial virus (EL-RSV) infection has been implicated in long-term pulmonary disease in children. In these studies, neonatal BALB/c mice were infected at day 7 of life, leading to >35% losses in critical lung function, airway mucus metaplasia, and transcriptional hallmarks of mucus hypersecretion four weeks after RSV infection. While EL-RSV minimally reshaped the resident lung microbiota, it led to significant gut dysbiosis, including a long-term reduction of Proteobacteria that can be a source of protective metabolites related to barrier and immune function. Subsequent studies assessing whether a common infant antibiotic (ampicillin) could mitigate EL-RSV-induced lung alterations revealed further severe gut microbiome alterations and, on its own, later in life, recapitulated the full spectrum of RSV-associated alterations in lung function. Metagenomic inference showed that both RSV and ampicillin administered during early life reduced biosynthetic pathways for microbiome-derived metabolites, which are known to reinforce tight junctions, regulate inflammation, and preserve extracellular matrix elasticity. The shared loss of these metabolic programs provides a mechanistic bridge linking distinct early-life exposures to the microbiome changes and airway mechanical deficits later in life. Collectively, the data suggest that RSV and/or antibiotic-triggered gut dysbiosis is the primary insult that likely promotes improper lung maturation/repair through a metabolite-mediated mechanism and may suggest metabolite restoration as a strategy to promote proper developmental lung function. Full article

E-cigarettes (E-cigs) are increasing in popularity and are considered a potentially safer alternative to traditional cigarettes. However, prior studies have demonstrated that inhalation of nicotine-containing e-cigs can cause substantial pathophysiologic changes, and “vaping” of some substances has led to severe lung damage. Our group recently described the role of cortactin (CTTN), a cytoskeletal actin-binding regulatory protein, in mediating cigarette smoke (CS) and E-cig-induced lung endothelial apoptosis and mitochondrial dysfunction. In the current study, we advance this work by characterizing the effects of E-cig on lung endothelial nanomechanical properties and barrier function. Lung EC exposure to E-cig extract (50 µg/mL) resulted in disruption of endothelial barrier properties as assessed by Electric Cell–Substrate Impedance Sensing (ECIS). Since excess mitochondrial reactive oxygen species (mitoROS) is an important marker of mitochondrial dysfunction, we next assessed the effect of Mito-TEMPO (10 µM, 3 h), a cell-permeable antioxidant, on E-cig-induced endothelial permeability. Pretreatment with Mito-TEMPO provided EC barrier protection after E-cig challenge, suggesting a key role of mitoROS in E-cig-induced EC permeability. E-cig exposure induces cytoskeleton rearrangement, leading to gap formation in lung EC, and significantly alters EC elastic properties as assessed by atomic force microscopy (AFM). Reduction in CTTN expression by siRNA further augmented the injurious effects of E-cig on EC permeability and elastic properties. This is the first study to explore the role of CTTN in evaluating the effect of E-cigarette exposure on the lung endothelium using AFM and provides novel mitochondrial and biophysical characterization of the effects of E-cig exposure on human lung EC. This work advances our understanding of the pathophysiologic effects of E-cig exposure. Full article

Pulmonary emphysema is a progressive and debilitating lung disease characterized by the destruction of alveolar walls and enlargement of airspaces, resulting in impaired gas exchange and reduced lung function. Central to this pathology is the degradation of the extracellular matrix (ECM), particularly the elastic fiber network containing elastin protein responsible for storing and releasing the energy that expels air from the lung. Both intrinsic and extrinsic mechanical stress play a pivotal role in ECM remodeling, influencing elastin degradation and the structural integrity of alveolar walls. This paper explores the interactions between mechanical forces and ECM components, emphasizing the role of increased elastin crosslinking in the pathogenesis and progression of emphysema. The molecular mechanisms responsible for this process are described in the context of emergent phenomena associated with alveolar wall distension and rupture, including the role of diagnostic biomarkers in the early detection of elastic fiber injury that may facilitate timely therapeutic interventions designed to preserve ECM integrity and improve patient outcomes. Full article

Karate is divided into two disciplines, Kata (forms) and Kumite (sparring), both of which are strongly influenced by the function of the tibiotarsal joint. However, the performance model differences between the two have not yet been thoroughly explored. The aim of this study is to evaluate the differences in ankle range of motion between Kata and Kumite, investigating the correlations between joint mobility, elastic strength, and Rate of Force Development (RFD). The sample consisted of 36 athletes, of male sex, evenly split between the two disciplines, who underwent a specific training protocol for three months. Three tests were administered: Weight Bearing Lunge, Counter Movement Jump, and Squat Jump. Data were analysed using Pearson’s correlation. In the Kata group, a moderate negative correlation emerged between ankle ROM and elastic strength (R = −0.521), and between ankle ROM and RFD (R = −0.570). In the Kumite group, the correlations were weakly negative: R = −0.261 for elastic strength and R = −0.257 for RFD. Greater ankle mobility, typical of Kata, appears to be associated with lower explosive capabilities, whereas more limited mobility in Kumite correlates with higher reactive strength and a faster rate of force development. Full article

This study investigates the influence of variable electrode positions on image reconstruction in capacitively coupled electrical impedance tomography (CC-EIT) of the human thorax. Images were reconstructed by an adversarial neural network trained on a synthetic dataset generated using a tomographic model that included a wearable elastic band with 32 electrodes attached. Dataset generation was conducted using a previously developed numerical phantom of the thorax, combined with a newly developed algorithm for random selection of electrode positions based on physical limitations resulting from the elasticity of the band and possible position inaccuracies while putting the band on the patient’s chest. The thorax phantom included the heart, lungs, aorta, and spine. Four training and four testing datasets were generated using four different levels of electrode displacement. Reconstruction was conducted using four versions of neural networks trained on the datasets, with random ellipses included and noise added to achieve an SNR of 30 dB. The quality was assessed using pixel-to-pixel metrics such as the root-mean-square error, structural similarity index, 2D correlation coefficient, and peak signal-to-noise ratio. The results showed a strong negative influence of electrode displacement on reconstruction quality when no samples with displaced electrodes were present in the training dataset. Training the network on the dataset containing samples with electrode displacement allowed us to significantly improve the quality of the reconstructed images. Introducing samples with misplaced electrodes increased neural network robustness to electrode displacement while testing. Full article

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin–angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular–pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1–7), angiotensin-converting enzyme 2 (ACE2), Bmpr2, Smad5 and nitrite (NO₂⁻) and nitrate (NO₃⁻) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1–7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1–7) (MAS) and ACE2. FF tended to restore Bmpr2/Smad5 expression. NO₂⁻ levels were preserved and tended to preserve (NO₃⁻) levels. In the RV, Ang-(1–7) increased, ACE2 was preserved, and NO₂⁻ and NO₃ levels were maintained. FF exerts protective effects in Su/Hx-induced PAH. Full article

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by irreversible alveolar destruction and pathological extracellular matrix (ECM) deposition. Currently approved agents (pirfenidone and nintedanib) slow functional decline but do not reverse established fibrosis or restore functional alveoli. Multifunctional bioscaffolds present a promising therapeutic strategy through targeted modulation of critical cellular processes, including proliferation, migration, and differentiation. This review synthesizes recent advances in scaffold-based interventions for PF, with a focus on their dual mechano-epigenetic regulatory functions. We delineate how scaffold properties (elastic modulus, stiffness gradients, dynamic mechanical cues) direct cell fate decisions via mechanotransduction pathways, exemplified by focal adhesion–cytoskeleton coupling. Critically, we highlight how pathological mechanical inputs establish and perpetuate self-reinforcing epigenetic barriers to regeneration through aberrant chromatin states. Furthermore, we examine scaffolds as platforms for precision epigenetic drug delivery, particularly controlled release of inhibitors targeting DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) to disrupt this mechano-reinforced barrier. Evidence from PF murine models and ex vivo lung slice cultures demonstrate scaffold-mediated remodeling of the fibrotic niche, with key studies reporting substantial reductions in collagen deposition and significant increases in alveolar epithelial cell markers following intervention. These quantitative outcomes highlight enhanced alveolar epithelial plasticity and upregulating antifibrotic gene networks. Emerging integration of stimuli-responsive biomaterials, CRISPR/dCas9-based epigenetic editors, and AI-driven design to enhance scaffold functionality is discussed. Collectively, multifunctional bioscaffolds hold significant potential for clinical translation by uniquely co-targeting mechanotransduction and epigenetic reprogramming. Future work will need to resolve persistent challenges, including the erasure of pathological mechanical memory and precise spatiotemporal control of epigenetic modifiers in vivo, to unlock their full therapeutic potential. Full article

Advances in additive manufacturing (AM) have revolutionized various sectors, including aerospace engineering, where the use of lattice structures has enabled the development of lightweight high-performance components with optimized mechanical properties. Building on these engineering principles, this study explores the application of aerospace-derived lattice design strategies to the biomedical field, specifically for the replication of human lung alveolar structures. The objective is to create anatomically accurate 3D-printed lung models suitable for surgical planning. Finite element analyses have been conducted using a CAD model of adult lungs, including the application of lattice structures generated through nTopology software, to evaluate the elasticity and density, critical for simulating lung mechanics. A preliminary prototype has been produced using stereolithography and flexible resin, showing the potential for realistic tactile feedback. Full article

Eggshell membrane (ESM) is composed of approximately 90% protein. Our previous studies in healthy adults demonstrated that two months of daily ESM intake improved respiratory function, zigzag walking speed, and skin elasticity. The present study aims to address the knowledge gap regarding the in vivo effects of ESM in the context of inflammatory bowel disease (IBD). Proteomic analysis was performed on powdered ESM used as a dietary supplement. To investigate its pharmacokinetics in mice, tritium (³H)-labeled ESM was prepared using the ⁶Li(n,α)³H nuclear reaction. The therapeutic potential of ESM was further examined in a 2.0% dextran sulfate sodium (DSS)-induced murine model of IBD. In addition, fecal samples from both mice and healthy human subjects were analyzed using a modified terminal restriction fragment length polymorphism (T-RFLP) method. Lysozyme C (LYZ) was the most abundant protein (47%), followed by lysyl oxidase (12%) in ESM used in this study. ³H-ESM was mixed with MediGel, and orally administered to mice. Radioactivity levels were measured in blood, organs (duodenum, small intestine, large intestine, liver, kidney, lung, skin), and rectal feces at 0.5, 2, 5, 24, 48, and 72 h post-administration. Radioactivity in feces indicated excretion of undigested components, while systemic distribution suggested potential whole-body effects of ESM. Oral ESM and LYZ significantly alleviated body weight loss, diarrhea, and hematochezia in a DSS-induced murine model of IBD, leading to a significantly lower disease activity index on day 3 and showing a similar trend on day 5. Gut microbiota analysis showed increased Bacteroidales in the DSS group, while the ESM + DSS group maintained levels similar to the control. In humans, a double-blind, randomized controlled trial was conducted to evaluate the effects of ESM on gut microbiota in healthy adults. Participants received either ESM or placebo for 8 weeks. revealed a significant increase in alpha diversity at weeks 1 and 8 in the ESM group (p < 0.05), with between-group differences evident from week 1 (p < 0.01). ESM intake reduced Bacteroides and significantly increased Bifidobacterium and Lactobacillales at weeks 4 and 8. These findings suggest ESM supplementation promotes beneficial modulation of gut microbiota. These findings suggest that ESM, through its major protein components such as LYZ, may serve as a promising dietary intervention for maintaining intestinal health and mitigating inflammation in the context of IBD. Full article

The concept of mechanical power (MP) has emerged as a comprehensive indicator of ventilator-induced lung injury (VILI). It integrates the effects of tidal volume, airway pressures, respiratory rate, and flow. However, applying MP as a universal threshold (e.g., 12 J/min) across heterogeneous patients with acute respiratory distress syndrome (ARDS) may be inadequate. This review introduces the rheological model, which conceptualizes the lung as a viscoelastic body (i.e., one that exhibits both elastic and viscous properties), and applies it to ARDS ventilation. The rheological model may offer individualized MP thresholds. The potential benefits of adjusting MP based on ideal body weight (J/min/kg) are discussed and, more accurately, on static compliance (J/min/L). Static compliance could better reflect functional lung size, though clinical validation remains needed. Preliminary clinical and modeling evidence suggests that normalized MP correlates more closely with mortality than absolute MP and aligns with pulmonary stress–strain behavior. This normalization provides a more precise risk stratification and facilitates the easier setting of ventilation targets, particularly in patients with low compliance or abnormal body composition. This review clarifies definitions and consolidates evidence, highlights the clinical implications of rheology for lung-protective strategies. MP normalization within a lung-protective strategy could enhance the safety and efficacy of mechanical ventilation; however, clinical validation is still required. This review summarizes the theoretical foundations, supporting evidence, and clinical implications of this approach within the broader context of rheological modeling in ARDS. Full article

Pulmonary emphysema, the main component of chronic obstructive pulmonary disease, is a chronic lung inflammatory disease characterized by the loss of lung elasticity and impaired gas exchange due in large part to the destruction of alveolar walls. Cigarette smoking represents the most frequent etiologic factor, but other factors involving environmental pollution and respiratory infections contribute to disease pathogenesis and worsening. In this review, we provide a review about emphysema covering risk factors; underlying mechanisms of disease pathogenesis; experimental models that mimic, as closely as possible, human disease features; and available therapeutics. Lastly, exploratory therapeutic approaches aimed at improving patient health through evidence-based and personalized medicine are presented as well. Full article

Animal models provide a controlled and reproducible environment for investigating the pathogenesis of human lung diseases. In many cases, the morphological changes associated with a particular model may resemble those seen in their human counterparts, but the corresponding biochemical events may differ, and their timeframe may be significantly reduced. Nevertheless, gaining insight into human disease mechanisms may be possible by employing experimental approaches that minimize the problems associated with extrapolating data from animal studies. Such strategies include using more than one model of a particular disease, employing different routes of administration of the injurious agent, using a variety of animal strains or species, or focusing on biochemical mechanisms common to both the animal model and its human counterpart. For example, rodent models that replicate elastic fiber injury in human pulmonary emphysema have been used to test aerosolized hyaluronan’s ability to slow the disease’s progression. The same models facilitated the identification of a new biomarker for pulmonary emphysema that may be a real-time indicator of therapeutic efficacy in clinical trials. Therefore, the appropriate use of these models can provide a necessary road map for designing appropriate dosages, delivery routes, timeframes, and endpoints in clinical trials of novel agents for the treatment of lung disease. Full article

Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung–brain axis. To investigate molecular mechanisms, adult male rats were exposed to filtered air, naphthalene (a representative volatile organic compound), or a combination of naphthalene and carbon black (surrogate for particulate matter; CBN) via whole-body inhalation (six hours/day, three consecutive days). Lung, brain, and plasma samples were collected 24 h after the final exposure. Pro-inflammatory biomarkers were assessed using multiplex electrochemiluminescence and western blot. Differentially expressed genes (DEGs) were identified by RNA sequencing, and elastic net modeling was used to define exposure-predictive gene signatures. CBN exposure altered inflammatory biomarkers across tissues, with activation of nuclear factor kappa B (NF-κB) signaling. In the lung, gene set enrichment revealed activated pathways related to proliferation and inflammation, while epithelial–mesenchymal transition (EMT) and oxidative phosphorylation were suppressed. In the brain, EMT, inflammation, and senescence pathways were activated, while ribosomal function and oxidative metabolism were downregulated. Elastic net modeling identified a lung gene signature predictive of CBN exposure, including Kcnq3, Tgfbr1, and Tm4sf19. These findings demonstrate that inhalation of a surrogate burn pit mixture induces inflammatory and metabolic gene expression changes in both lung and brain tissues, supporting the utility of this animal model for understanding systemic effects of airborne military toxicants and for identifying potential biomarkers relevant to DRRD and Veteran health. Full article