Search Results (910)

Hypothermia-related deaths present significant diagnostic challenges due to non-specific and often inconsistent autopsy findings. This study investigated the histological and immunohistochemical alterations associated with primary and secondary hypothermia in an experimental Rattus norvegicus model, focusing on the effects of benzodiazepine and alcohol ingestion. Twenty-one male rats were divided into three groups: control (K), benzodiazepine-treated (B), and alcohol-treated (A). After two weeks of substance administration, hypothermia was induced and multiple organ samples were analyzed. Histologically, renal tissue showed hydropic and vacuolar degeneration, congestion, and acute tubular injury across all groups, with no significant differences in E-cadherin expression. Lung samples revealed congestion, emphysema, and hemorrhage, with more pronounced vascular congestion in the alcohol and benzodiazepine groups. Cardiac tissue exhibited vacuolar degeneration and protein denaturation, particularly in substance-exposed animals. The spleen showed preserved architecture but increased erythrocyte infiltration and significantly elevated myeloperoxidase (MPO)-positive granulocytes in the intoxicated groups. Liver samples demonstrated congestion, focal necrosis, and subcapsular hemorrhage, especially in the alcohol group. Immunohistochemical analysis revealed statistically significant differences in MPO expression in both lung and spleen tissues, with the highest levels observed in the benzodiazepine group. Similarly, CK7 and CK20 expression in the gastroesophageal junction was significantly elevated in both alcohol- and benzodiazepine-treated animals compared to the controls. In contrast, E-cadherin expression in the kidney did not differ significantly among the groups. These findings suggest that specific histological and immunohistochemical patterns, particularly involving pulmonary, cardiac, hepatic, and splenic tissues, may help differentiate primary hypothermia from substance-related secondary hypothermia. The study underscores the value of integrating toxicological, histological, and molecular analyses to enhance the forensic assessment of hypothermia-related fatalities. Future research should aim to validate these markers in human autopsy series and explore additional molecular indicators to refine diagnostic accuracy in forensic pathology. Full article

Fat embolism is a critical medical emergency often resulting from long bone fractures or amputations, leading to acute respiratory distress syndrome (ARDS). The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity, is activated by reactive oxygen species and tissue damage, contributing to inflammatory responses. This study examines the role of NLRP3 in fat embolism-induced ARDS and evaluates the therapeutic potential of MCC950, a selective NLRP3 antagonist. Fat embolism was induced by fatty micelle injection into the tail vein of Sprague Dawley rats. Pulmonary injury was assessed through lung weight gain as an edema indicator, NLRP3 expression via Western blot, and IL-1β levels using ELISA. Histological damage and macrophage infiltration were evaluated with hematoxylin and eosin staining. Fat embolism significantly increased pulmonary NLRP3 expression, lipid peroxidation, IL-1β release, and macrophage infiltration within four hours, accompanied by severe pulmonary edema. NLRP3 was localized in type I alveolar cells, co-localizing with aquaporin 5. Administration of MCC950 significantly reduced inflammatory responses, lipid peroxidation, pulmonary edema, and histological damage, while attenuating MAPK cascade phosphorylation of ERK and Raf. These findings suggest that NLRP3 plays a critical role in fat embolism-induced acute respiratory distress syndrome, and its inhibition by MCC950 may offer a promising therapeutic approach. Full article

Background: Acute mountain sickness (AMS) is a prevalent and potentially life-threatening condition caused by rapid exposure to high-altitude hypoxia, affecting pulmonary and neurological functions. Tongqiao Jiuxin Oil (TQ), a traditional Chinese medicine formula composed of aromatic and resinous ingredients such as sandalwood, agarwood, frankincense, borneol, and musk, has been widely used in the treatment of cardiovascular and cerebrovascular disorders. Clinical observations suggest its potential efficacy against AMS, yet its pharmacological mechanisms remain poorly understood. Methods: The chemical profile of TQ was characterized using UHPLC-Q-Exactive Orbitrap HRMS. Network pharmacology was applied to predict the potential targets and pathways involved in AMS. A rat model of AMS was established by exposing animals to hypobaric hypoxia (~10% oxygen), simulating an altitude of approximately 5500 m. TQ was administered at varying doses. Physiological indices, oxidative stress markers (MDA, SOD, GSH), histopathological changes, and the expression of hypoxia- and apoptosis-related proteins (HIF-1α, VEGFA, EPO, Bax, Bcl-2, Caspase-3) in lung and brain tissues were assessed. Results: A total of 774 chemical constituents were identified from TQ. Network pharmacology predicted the involvement of multiple targets and pathways. TQ significantly improved arterial oxygenation and reduced histopathological damage in both lung and brain tissues. It enhanced antioxidant activity by elevating SOD and GSH levels and reducing MDA content. Mechanistically, TQ downregulated the expression of HIF-1α, VEGFA, EPO, and pro-apoptotic markers (Bax/Bcl-2 ratio, Caspase-3), while upregulated Bcl-2, the anti-apoptotic protein expression. Conclusions: TQ exerts protective effects against AMS-induced tissue injury by improving oxygen homeostasis, alleviating oxidative stress, and modulating hypoxia-related and apoptotic signaling pathways. This study provides pharmacological evidence supporting the potential of TQ as a promising candidate for AMS intervention, as well as the modern research method for multi-component traditional Chinese medicine. Full article

Fine particulate matter (PM_2.5) exposure has been linked to increased lung damage due to compromised vascular barrier function, while 3-deoxysappanchalcone (3-DSC), a chalcone derived from Caesalpinia sappan, is known for its pharmacological benefits such as anti-cancer, anti-inflammatory, and antioxidant effects; however, its potential role in mitigating PM_2.5-induced pulmonary damage remains unexplored. To confirm the inhibitory effects of 3-DSC on PM_2.5-induced pulmonary injury, this research focused on evaluating how 3-DSC influences PM_2.5-induced disruption of the barrier of the endothelial cells (ECs) in the lungs and the resulting pulmonary inflammation. Permeability, leukocyte migration, proinflammatory protein activation, reactive oxygen species (ROS) generation, and histology were assessed in PM_2.5-treated ECs and mice. This study demonstrated that 3-DSC effectively neutralized the reactive oxygen species (ROS) generated by PM_2.5 exposure in the lung endothelial cells, suppressing ROS-triggered p38 MAPK activation while enhancing Akt signaling pathways critical to preserving vascular barrier function. In animal models, 3-DSC administration markedly decreased vascular permeability, attenuated the influx of immune cells into the lung tissue, and lowered inflammatory mediators like cytokines in the airways of PM_2.5-exposed mice. These data suggest that 3-DSC might exert protective effects on PM_2.5-induced inflammatory lung injury and vascular hyperpermeability. Full article

Background/Objectives: Acute kidney injury (AKI) worsens outcomes in COPD exacerbation (COPDe), yet limited data compare the demographics and mortality risk factors of COPDe admissions with and without AKI. Understanding this association may enhance risk stratification and management strategies. The aim of this study was to identify demographic differences and mortality risk factors in COPDe admissions with and without AKI. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (NIS) from 1 January 2016 to 1 January 2021. Patients aged ≥ 35 years with a history of smoking and a diagnosis of COPDe were included. Patients with CKD stage 5, end-stage kidney disease (ESKD), heart failure decompensation, urinary tract infections, myocardial infarction, alpha-1 antitrypsin deficiency, or active COVID-19 infection were excluded. Baseline demographics were analyzed using descriptive statistics. Multivariate logistic regression analysis was used to measure the odds ratio (OR) of mortality. Statistical analyses were conducted using IBM SPSS Statistics V.30, with statistical significance at p < 0.05. Results: Among 405,845 hospitalized COPDe patients, 13.6% had AKI. These patients were older, had longer hospital stays, and included fewer females and White patients. AKI was associated with significantly higher mortality (OR: 2.417), more frequent acute respiratory failure (OR: 4.559), intubation (OR: 10.262), and vasopressor use (OR: 2.736). CVA, pneumonia, and pulmonary hypertension were significant mortality predictors. Hypertension, CAD, and diabetes were associated with lower mortality. Conclusions: AKI in COPDe admissions is associated with worse outcomes. Protective effects from certain comorbidities may relate to renoprotective medications. Study limitations include coding errors and retrospective design. Full article

Plasmodium falciparum malaria remains a major cause of morbidity and mortality, particularly in endemic regions. We report the case of a 21-year-old male with recent travel to an endemic area (Guapi, Colombia), who presented with febrile symptoms, severe respiratory distress, and oxygen saturation below 75%, necessitating orotracheal intubation. During the procedure, he developed pulseless electrical activity cardiac arrest, achieving return of spontaneous circulation after advanced resuscitation. Diagnosis was confirmed by thick blood smear, demonstrating P. falciparum infection. The patient progressed to multiorgan failure, including acute respiratory distress syndrome with capillary leak pulmonary edema, refractory distributive shock, acute kidney injury with severe hyperkalemia, and consumptive thrombocytopenia. Management included invasive mechanical ventilation, vasopressor support, sedation-analgesia, neuromuscular blockade, methylene blue, unsuccessful hemodialysis due to hemorrhagic complications, and platelet transfusions. Despite these interventions, the patient experienced a second cardiac arrest and died. This case highlights the severity and rapid progression of severe malaria with multisystem involvement, underscoring the critical importance of early diagnosis and intensive multidisciplinary management. It also emphasizes the need for preventive strategies for travelers to endemic areas and the development of clinical protocols to improve outcomes in complicated malaria. Full article

Background: Pulsed field ablation (PFA) is a novel non-thermal modality for pulmonary vein isolation (PVI) in atrial fibrillation (AF), offering myocardial selectivity through irreversible electroporation while sparing surrounding structures. However, concerns have emerged regarding potential subclinical hemolysis, reflected by alterations in biochemical markers such as lactate dehydrogenase (LDH). Methods: We conducted a retrospective, single-center study involving 249 patients undergoing PVI: 121 treated with PFA (PulseSelect or FARAPULSE) and 128 with radiofrequency (RF) ablation (PVAC catheter). Laboratory parameters were assessed at baseline, post-procedure, and at discharge, including hemoglobin, hematocrit, red blood cell (RBC) count, platelet count, creatinine, and LDH. The primary endpoint was the variation in blood cell indices; the secondary endpoint was the evaluation of LDH and hematocrit changes. Statistical analysis included t-tests and chi-square tests. Results: Baseline characteristics and pre-procedural labs did not differ significantly between groups. No significant changes in hemoglobin, hematocrit, RBC count, platelet count, or creatinine were observed post-ablation or at discharge. However, LDH levels significantly increased in the PFA group both post-procedurally and at discharge (p < 0.001), without concurrent changes in other blood cell parameters. Conclusions: PFA and RF ablation yield comparable hematological profiles after PVI, with no significant impact on key blood cell parameters. Nonetheless, the consistent rise in LDH levels in the PFA group suggests mild, subclinical hemolysis or tissue injury due to more extensive lesions. While supporting the hematologic safety of PFA, these findings underscore the need for further studies to assess the clinical significance of these biochemical alterations, particularly in high-risk patients or extensive ablation settings. Full article

Cadmium (Cd)-induced pulmonary toxicity is closely associated with ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation (LPO). Luteolin (Lut) is a natural flavonoid compound that exists in many plants. In this study, we used human bronchial epithelial BEAS-2B cells to explore the impact of ferroptosis in the inhibition of Cd-induced BEAS-2B cells proliferation. BEAS-2B cells were exposed to Cd (5 μM) with/without Lut (10 μM), ferroptosis modulators (Ferrostatin-1 (Fer-1)/Erastin), or nuclear factor erythroid 2-related factor 2 (Nrf2) regulators (tert-butylhydroquinone (TBHQ)/ML385). Viability, iron content, reactive oxygen species (ROS), LPO, mitochondrial membrane potential (MMP), and glutathione peroxidase (GSH-PX) activity were assessed. Exposure to Cd significantly decreased cell viability, increased intracellular iron levels, ROS production, and LPO activity, while simultaneously reducing MMP and GSH-PX activity. Fer-1 mitigated Cd-induced cytotoxicity, but Erastin intensified these effects. Mechanistically, Cd exposure suppressed the Nrf2/Solute Carrier Family 7 Member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway, which plays a crucial role in maintaining redox homeostasis. Activation of Nrf2 using TBHQ mitigated oxidative stress and upregulated the expression of key proteins within this pathway, while inhibition of Nrf2 with ML385 exacerbated cellular damage. Notably, Lut treatment could significantly alleviate Cd-induced cytotoxicity, oxidative stress, and downregulation of Nrf2/SLC7A11/GPX4 proteins. These findings demonstrate that ferroptosis is a critical mechanism underlying Cd-mediated lung epithelial injury and identify Lut as a promising therapeutic candidate via its activation of Nrf2-driven antioxidant defense mechanisms. This study provides novel insights into molecular targets for the prevention and treatment of Cd-associated pulmonary disorders. Full article

Background: The study evaluates the immunomodulatory potential of secukinumab (SECU) and honokiol (HONK) in a murine model of allergic asthma complicated by acute lung injury (ALI), with an emphasis on modulating key inflammatory pathways. The rationale is driven by the necessity to attenuate Th17-mediated cytokine cascades, wherein IL-17 plays a critical role, as well as to explore the adjunctive anti-inflammatory effects of HONK on Th1 cytokine production, including IL-6, TNF-α, and Th2 cytokines. Methods: Mice were sensitized and challenged with ovalbumin (OVA) and lipopolysaccharide (LPS) was administrated to exacerbate pulmonary pathology, followed by administration of SECU, HONK (98% purity, C₁₈H₁₈O₂), or their combination. Quantitative analyses incorporated OVA-specific IgE measurements, differential cell counts in bronchoalveolar lavage fluid (BALF), and extensive cytokine profiling in both BALF and lung tissue homogenates, utilizing precise immunoassays and histopathological scoring systems. Results: Both SECU and HONK, when used alone or in combination, display significant immunomodulatory effects in a murine model of allergic asthma concomitant with ALI. The combined therapy synergistically reduced pro-inflammatory mediators, notably Th1 cytokines, such as TNF-α and IL-6, as measured in both BALF and lung tissue homogenates. Conclusions: The combined therapy showed a synergistic attenuation of pro-inflammatory mediators, a reduction in goblet cell hyperplasia, and an overall improvement in lung histoarchitecture. While the data robustly support the merit of a combinatorial approach targeting multiple inflammatory mediators, the study acknowledges limitations in cytokine diffusion and the murine model’s translational fidelity, thereby underscoring the need for further research to optimize clinical protocols for severe respiratory inflammatory disorders. Full article

Acute respiratory distress syndrome (ARDS) is an inflammatory pulmonary condition that remains at alarming rates of fatality, with neutrophils playing a vital role in its pathogenesis. Beyond their classical antimicrobial functions, neutrophils contribute to pulmonary injury via the release of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs). To identify targets for treatment, it was found that epigenetic mechanisms, including histone modifications, hypomethylation, hypermethylation, and non-coding RNAs, regulate neutrophil phenotypic plasticity, survival, and inflammatory potential. It has been identified that neutrophils in ARDS patients exhibit abnormal methylation patterns and are associated with altered gene expression and prolonged neutrophil activation, thereby contributing to sustained inflammation. Histone citrullination, particularly via PAD4, facilitates NETosis, while histone acetylation status modulates chromatin accessibility and inflammatory gene expression. MicroRNAs have also been shown to regulate neutrophil activity, with miR-223 and miR-146a potentially being biomarkers and therapeutic targets. Neutrophil heterogeneity, as evidenced by distinct subsets such as low-density neutrophils (LDNs), varies across ARDS etiologies, including COVID-19. Single-cell RNA sequencing analyses, including the use of trajectory analysis, have revealed transcriptionally distinct neutrophil clusters with differential activation states. These studies support the use of epigenetic inhibitors, including PAD4, HDAC, and DNMT modulators, in therapeutic intervention. While the field has been enlightened with new findings, challenges in translational application remain an issue due to species differences, lack of stratification tools, and heterogeneity in ARDS presentation. This review describes how targeting neutrophil epigenetic regulators could help regulate hyperinflammation, making epigenetic modulation a promising area for precision therapeutics in ARDS. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease characterized by chronic inflammation, vascular remodeling, and immune dysregulation. COVID-19, caused by SARS-CoV-2, shares several systemic immunohematologic disturbances with IPF, including cytokine storms, endothelial injury, and prothrombotic states. Unlike general comparisons of viral infections and chronic lung disease, this review offers a focused analysis of the shared hematologic and immunologic mechanisms between COVID-19 and IPF. Our aim is to better understand how SARS-CoV-2 infection may worsen disease progression in IPF and identify converging pathophysiological pathways that may inform clinical management. We conducted a narrative synthesis of the peer-reviewed literature from PubMed, Scopus, and Web of Science, focusing on clinical, experimental, and pathological studies addressing immune and coagulation abnormalities in both COVID-19 and IPF. Both diseases exhibit significant overlap in inflammatory and fibrotic signaling, particularly via the TGF-β, IL-6, and TNF-α pathways. COVID-19 amplifies coagulation disturbances and endothelial dysfunction already present in IPF, promoting microvascular thrombosis and acute exacerbations. Myeloid cell overactivation, impaired lymphocyte responses, and fibroblast proliferation are central to this shared pathophysiology. These synergistic mechanisms may accelerate fibrosis and increase mortality risk in IPF patients infected with SARS-CoV-2. This review proposes an integrative framework for understanding the hematologic and immunologic convergence of COVID-19 and IPF. Such insights are essential for refining therapeutic targets, improving prognostic stratification, and guiding early interventions in this high-risk population. Full article

Objectives: COVID-19, caused by the SARS-CoV-2 virus, has infected over 777 million individuals and led to approximately 7 million deaths worldwide. Despite significant efforts to develop effective therapies, treatment remains largely supportive, especially for severe complications like acute respiratory distress syndrome (ARDS). Numerous compounds from diverse pharmacological classes are currently undergoing preclinical and clinical evaluation, targeting both the virus and the host immune response. Methods: Despite the large number of articles published and after a preliminary attempt was published, we discarded the option of a systematic review. Instead, we have done a description of therapies with these results and a tentative mechanism of action. Results: Preliminary studies and early-phase clinical trials have demonstrated the potential of Mesenchymal Stem Cells (MSCs) in mitigating severe lung damage in COVID-19 patients. Previous research has shown MSCs to be effective in treating various pulmonary conditions, including acute lung injury, idiopathic pulmonary fibrosis, ARDS, asthma, chronic obstructive pulmonary disease, and lung cancer. Their ability to reduce inflammation and promote tissue repair supports their potential role in managing COVID-19-related complications. This review demonstrates the utility of MSCs in the acute phase of COVID-19 and postulates the etiopathogenic role of mitochondria in Long-COVID. Even more, their combination with other therapies is also analyzed. Conclusions: While the therapeutic application of MSCs in COVID-19 is still in early stages, emerging evidence suggests promising outcomes. As research advances, MSCs may become an integral part of treatment strategies for severe COVID-19, particularly in addressing immune-related lung injury and promoting recovery. However, a full pathogenic mechanism may explain or unify the complexity of signs and symptoms of Long COVID and Post-Acute Sequelae (PASC). Full article

Objectives: Saffron, a traditional Chinese medicine, is renowned for its pharmacological effects in promoting blood circulation, resolving blood stasis, regulating menstruation, detoxification, and alleviating mental disturbances. Trans-crocetin, its principal bioactive component, exhibits significant anti-hypoxic activity. The clinical development and therapeutic efficacy of trans-crocetin are limited by its instability, poor solubility, and low bioavailability. Conversion of trans-crocetin into trans-sodium crocetinate (TSC) enhances its solubility, stability, and bioavailability, thereby amplifying its anti-hypoxic potential. Methods: This study integrates network pharmacology with in vivo and in vitro validation to elucidate the molecular targets and mechanisms underlying TSC’s therapeutic effects against high-altitude acute lung injury (HALI), aiming to identify novel treatment strategies. Results: TSC effectively reversed hypoxia-induced biochemical abnormalities, ameliorated lung histopathological damage, and suppressed systemic inflammation and oxidative stress in HALI rats. In vitro, TSC mitigated CoCl₂-induced hypoxia injury in human pulmonary microvascular endothelial cells (HPMECs) by reducing inflammatory cytokines, oxidative stress, and ROS accumulation while restoring mitochondrial membrane potential. Network pharmacology and pathway analysis revealed that TSC primarily targets the EGFR/PI3K/AKT/NF-κB signaling axis. Molecular docking and dynamics simulations demonstrated stable binding interactions between TSC and key components of this pathway. ELISA and RT-qPCR confirmed that TSC significantly downregulated the expression of EGFR, PI3K, AKT, NF-κB, and their associated mRNAs. Conclusions: TSC alleviates high-altitude hypoxia-induced lung injury by inhibiting the EGFR/PI3K/AKT/NF-κB signaling pathway, thereby attenuating inflammatory responses, oxidative stress, and restoring mitochondrial function. These findings highlight TSC as a promising therapeutic agent for HALI. Full article

Increased epithelial and endothelial permeability, along with dysregulated inflammatory responses, are key aspects of acute respiratory distress syndrome (ARDS) pathophysiology, which not only impact the lungs but also contribute to detrimental organ crosstalk with distant organs, ultimately leading to multiple organ dysfunction syndrome (MODS)—the primary cause of morbidity and mortality in patients with lung injury (LI) and ARDS. It is predominantly manifested by hypoxemic respiratory failure and bilateral pulmonary infiltrates, which cannot be fully attributed to cardiac failure or hypervolemia, but rather to alveolo-capillary barrier dysfunction, dysregulated systemic and pulmonary inflammation, immune system abnormalities, and mechanical stimuli-related responses. However, these pathological features are not uniform among patients with ARDS, as distinct subphenotypes with unique biological, clinical, physiological, and radiographic characteristics have been increasingly recognized in recent decades. The severity of ARDS, clinical outcomes, mortality, and efficacy of applied therapeutic measures appear significant depending on the respective phenotype. Acknowledging the heterogeneity of ARDS and defining distinct subphenotypes could significantly modify therapeutic strategies, enabling more precise and targeted treatments. To address these issues, a comprehensive literature search was conducted in PubMed using predefined keywords related to ARDS pathophysiology, subphenotypes, and personalized therapeutic approaches. Optimizing the identification and characterization of discrete ARDS subphenotypes—based on clinical, biological, physiological, and radiographic criteria—will deepen our understanding of ARDS pathophysiology, promote targeted recruitment in prospective clinical studies to define patient clusters with heterogeneous therapeutic responses, and support the shift toward individualized treatment strategies. Full article

Despite the prevalence of fucosylated IgG in plasma, specific IgGs with low core fucosylation sporadically emerge in response to virus infections and blood cell alloantigens. This low fucosylation of IgG is implicated in the pathogenesis of SARS-CoV-2 and dengue infections. In COVID-19, the presence of IgGs with low core fucosylation (afucosylated IgGs) targeting spike protein predicts disease progression to a severe form and actively mediates this progression. This study reveals that SARS-CoV-2 infection of megakaryocytes promotes the generation of pathogenic afucosylated anti-spike IgGs, leading to outcomes, such as pulmonary vascular thrombosis, acute lung injury, and mortality in FcγRIIa-transgenic mice. Platelets from mice injected with virus-infected human megakaryocytes express significant activation biomarkers, indicating a direct link between the immune response and platelet activation. Mice injected with virus-infected human megakaryocytes demonstrate an elevated rate of thrombus formation induced by FeCl₃ (4%) and a reduction in bleeding time, emphasizing the intricate interplay of viral infection, immune response, and hemostatic complications. Treatment with inhibitors targeting FcγRIIa, serotonin, or complement anaphylatoxins of mice injected with spike-expressing MKs successfully prevents observed platelet activation, thrombus formation, and bleeding abnormalities, offering potential therapeutic strategies for managing severe outcomes associated with afucosylated IgGs in COVID-19 and related disorders. Full article