Pathophysiology Of Acute Respiratory Distress Syndrome Research Articles

Exploring the lung-gut direction of the gut-lung axis in patients with ARDS.

Acute respiratory distress syndrome (ARDS) represents a life-threatening inflammatory reaction marked by refractory hypoxaemia and pulmonary oedema. Despite advancements in treatment perspectives, ARDS still carries a high mortality rate, often due to systemic inflammatory responses leading to multiple organ dysfunction syndrome(MODS). Indeed, the deterioration and associated mortality in patients with acute lung injury (LI)/ARDS is believed to originate alongside respiratory failure mainly from the involvement of extrapulmonary organs, a consequence of the complex interaction between initial inflammatory cascades related to the primary event and ongoing mechanical ventilation-induced injury resulting in multiple organ failure (MOF)and potentially death. Even though recent research has increasingly highlighted the role of the gastrointestinal tract in this process, the pathophysiology of gut dysfunction in patients with ARDS remains mainly underexplored. This review aims to elucidate the complex interplay between lung and gut in patients with LI/ARDS. We will examine various factors, including systemic inflammation, epithelial barrier dysfunction, the effects of mechanical ventilation (MV), hypercapnia, and gut dysbiosis. Understanding these factors and their interaction may provide valuable insights into the pathophysiology of ARDS and potential therapeutic strategies to improve patient outcomes.

Bronchoalveolar Lavage and Oleic Acid Two-hit Model for Inducing Acute Respiratory Distress Syndrome in Swine Models.

Acute respiratory distress syndrome (ARDS) is a widespread and often fatal clinical syndrome marked by the acute onset of pulmonary edema and inflammatory-mediated disruptions in alveolar-capillary permeability resulting in impaired gas exchange and tissue oxygenation with subsequent acute respiratory failure that accounts for 10.4% of all intensive care unit admissions worldwide and boasts a mortality rate of 38.5%. The current treatment for ARDS remains largely supportive. This is largely because of the many challenges of achieving a stable and sustainable animal model that recreates the pathophysiology of ARDS experimentally in a controlled setting to allow research to elucidate potential treatments of ARDS moving forward. The bronchoalveolar lavage and oleic acid models are currently the 2 most frequently used experimental models in inducing ARDS in animal models. This study demonstrated that combining them into a "two-hit model" can produce sustained ARDS in swine models per the Horowitz index (PaO2/FiO2 ratio of ≤300 mmHg). Additionally, expected changes in pH, pCO2, lung compliance, cytokines, and tissue histopathology were observed and add to our confidence and reliability that the "two-hit model" produces symptomatic ARDS in a manner very similar to that observed in humans. In conclusion, we demonstrated a viable animal model of human ARDS that is maintained for a prolonged period, suitable for continuous monitoring of the progression, and evaluation of potential future treatments and procedures to reduce patient morbidity and mortality. To carry out this two-hit model, lung injury was induced through a combination of bronchoalveolar lavage and oleic acid administration and the disease process of ARDS is subsequently tracked through clinically relevant parameters such as respiratory mechanics, cytokine response, aretrial blood gas (ABG) changes, and observation of postmortem histopathologic changes. This promising new model has the capacity to successfully replicate human ARDS which is a well-known and notoriously multifactorial pathogenic process to reproduce experimentally for an extended period of time. The "two-hit model" is a viable and appropriate model for the research of novel treatments for ARDS.

Functional roles of CD26/DPP4 in lipopolysaccharide-induced lung injury.

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells. In LPS-induced lung injury, inflammatory responses [bronchoalveolar lavage fluid (BALF) neutrophil numbers and several proinflammatory cytokine levels] were attenuated in Dpp4 knockout (Dpp4 KO) mice. However, multiple assays of alveolar capillary permeability were similar between the Dpp4 KO and wild-type mice. TNF-α and IL-6 production was suppressed in alveolar macrophages isolated from Dpp4 KO mice. In contrast, in cultured mouse lung microvascular endothelial cells (MLMVECs), reduction in CD26/DPP4 expression by siRNA resulted in greater ICAM-1 and IL-6 expression after LPS stimulation. Moreover, the LPS-induced vascular monolayer permeability in vitro was higher in MLMVECs treated with Dpp4 siRNA, suggesting that CD26/DPP4 plays a protective role in endothelial barrier function. In summary, this study demonstrated that genetic deficiency of Dpp4 attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential functional roles of CD26/DPP4 expression in resident cellular components of the lung. CD26/DPP4 may be a potential therapeutic target for ARDS and warrants further exploration to precisely identify the multiple functional effects of CD26/DPP4 in ARDS pathophysiology.NEW & NOTEWORTHY We aimed to clarify the functional roles of CD26/DPP4 in ARDS pathophysiology using Dpp4-deficient mice and siRNA reduction techniques in cultured lung cells. Our results suggest that CD26/DPP4 expression plays a proinflammatory role in alveolar macrophages while also playing a protective role in the endothelial barrier. Dpp4 genetic deficiency attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential roles of CD26/DPP4 expression in the resident cellular components of the lung.

ELUCIDATING THE MECHANISMS OF NEUTROPHIL EXTRACELLULAR TRAPS IN ACUTE RESPIRATORY DISTRESS SYNDROME PATHOGENESIS

This article critically examines the scientific literature related to the formation of neutrophil extracellular traps and their impact on the pathogenesis and clinical course of acute respiratory distress syndrome (ARDS). The available evidence indicates that the formation and accumulation of neutrophil extracellular traps in the lung tissue are implicated in the development and progression of ARDS. Moreover, recent studies have shed light on the potential mechanisms by which neutrophil extracellular traps contribute to impaired ventilationperfusion relationships in ARDS. The findings presented in this review suggest that further research into the phenomenon of neutrophil extracellular traps may lead to new insights into the pathophysiology of ARDS and inform the development of novel therapeutic strategies. Specifically, targeting neutrophil extracellular traps may offer a promising approach to attenuate the severity of ARDS and improve clinical outcomes. However, the complexity of the underlying mechanisms and the heterogeneity of ARDS patients necessitate further investigation to identify optimal therapeutic targets and treatment strategies.

Revisiting the Pathophysiology of Acute Respiratory Distress Syndrome in Burn with Inhalation Injury: A Comprehensive Review

Acute respiratory distress syndrome (ARDS) is a common complication in severe burn patients, arising from inflammatory responses following burns or inhalation injuries. This literature review explores the mechanisms and diagnostic approaches for ARDS in burn patients. Methods involved searching open-access journals using specific keywords on PubMed, Google Scholar, and Elsevier. The review highlights the involvement of various immune cells and cytokines in ARDS pathophysiology, with diagnostic tools including clinical signs, imaging, and bronchoscopy. Therapeutic strategies focus on ventilation and pharmacological interventions targeting inflammation. Further research is needed to better understand ARDS in burn patients, particularly regarding inflammatory markers and pharmacological treatments.

Tiny Guides, Big Impact: Focus on the Opportunities and Challenges of miR-Based Treatments for ARDS.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and increased membrane permeability, which represents the leading cause of mortality in ICUs. Mechanical ventilation strategies are at the forefront of supportive approaches for ARDS. Recently, an increasing understanding of RNA biology, function, and regulation, as well as the success of RNA vaccines, has spurred enthusiasm for the emergence of novel RNA-based therapeutics. The most common types of RNA seen in development are silencing (si)RNAs, antisense oligonucleotide therapy (ASO), and messenger (m)RNAs that collectively account for 80% of the RNA therapeutics pipeline. These three RNA platforms are the most mature, with approved products and demonstrated commercial success. Most recently, miRNAs have emerged as pivotal regulators of gene expression. Their dysregulation in various clinical conditions offers insights into ARDS pathogenesis and offers the innovative possibility of using microRNAs as targeted therapy. This review synthesizes the current state of the literature to contextualize the therapeutic potential of miRNA modulation. It considers the potential for miR-based therapeutics as a nuanced approach that incorporates the complexity of ARDS pathophysiology and the multifaceted nature of miRNA interactions.

Extracellular vesicles in acute respiratory distress syndrome: Understanding protective and harmful signaling for the development of new therapeutics.

Acute respiratory distress syndrome (ARDS) is a severe respiratory condition characterized by increased lung permeability, hyper-inflammatory state, and fluid leak into the alveolar spaces. ARDS is a heterogeneous disease, with multiple direct and indirect causes that result in a mortality of up to 40%. Due to the ongoing Covid-19 pandemic, its incidence has increased up to ten-fold. Extracellular vesicles (EVs) are small liposome-like particles that mediate intercellular communication and play a major role in ARDS pathophysiology. Indeed, they participate in endothelial barrier dysfunction and permeability, neutrophil, and macrophage activation, and also in the development of a hypercoagulable state. A more thorough understanding of the variegated and cell-specific functions of EVs may lead to the development of safe and effective therapeutics. In this review, we have collected evidence of EVs role in ARDS, revise the main mechanisms of production and internalization and summarize the current therapeutical approaches that have shown the ability to modulate EV signaling.

Pathophysiology of Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a common condition in intensive care medicine. Various intra- and extrapulmonal causes may trigger an epithelial and endothelial permeability increase, which leads to impaired gas exchange due to fluid overload of the alveoli and transmigration of leukocytes. This results in hypoxemia and hypercapnia, as well as deleterious consequences for the macro- and microcirculation with the risk of multi-organ failure and high mortality. This review summarizes ARDS pathophysiology and clinical consequences.

Lactobacillus rhamnosus (LR) ameliorates pulmonary and extrapulmonary acute respiratory distress syndrome (ARDS) via targeting neutrophils

Pulmonary and extrapulmonary acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure associated with high mortality. Despite progress in our understanding of the pathological mechanism causing the crippling illness, there are currently no targeted pharmaceutical treatments available for it. Recent discoveries have emphasized the existence of a potential nexus between gut and lung health fueling novel approaches including probiotics for the treatment of ARDS. We thus investigated the prophylactic-potential of Lactobacillus rhamnosus-(LR) in lipopolysaccharide (LPS)-induced pulmonary and cecal ligation puncture (CLP) induced extrapulmonary ARDS mice. Our in-vivo findings revealed that pretreatment with LR significantly ameliorated vascular-permeability (edema) of the lungs via modulating the neutrophils along with significantly reducing the expression of inflammatory-cytokines in the BALF, lungs and serum in both pulmonary and extrapulmonary mice-models. Interestingly, our ex-vivo immunofluorescence and flow cytometric data suggested that mechanistically LR via short chain fatty acids (butyrate being the most potent and efficient in ameliorating the pathophysiology of both pulmonary and extra-pulmonary ARDS) targets the phagocytic and neutrophils extracellular traps (NETs) releasing potential of neutrophils. Moreover, our in-vivo data further corroborated our ex-vivo findings and suggested that butyrate exhibits enhanced potential in ameliorating the pathophysiology of ARDS via reducing the infiltration of neutrophils into the lungs. Altogether, our study establishes the prophylactic role of LR and its associated metabolites in the prevention and management of both pulmonary and extrapulmonary ARDS via targeting neutrophils.

Reactive Oxygen Species and Strategies for Antioxidant Intervention in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary condition characterized by the sudden onset of respiratory failure, pulmonary edema, dysfunction of endothelial and epithelial barriers, and the activation of inflammatory cascades. Despite the increasing number of deaths attributed to ARDS, a comprehensive therapeutic approach for managing patients with ARDS remains elusive. To elucidate the pathological mechanisms underlying ARDS, numerous studies have employed various preclinical models, often utilizing lipopolysaccharide as the ARDS inducer. Accumulating evidence emphasizes the pivotal role of reactive oxygen species (ROS) in the pathophysiology of ARDS. Both preclinical and clinical investigations have asserted the potential of antioxidants in ameliorating ARDS. This review focuses on various sources of ROS, including NADPH oxidase, uncoupled endothelial nitric oxide synthase, cytochrome P450, and xanthine oxidase, and provides a comprehensive overview of their roles in ARDS. Additionally, we discuss the potential of using antioxidants as a strategy for treating ARDS.

ARDS (Acute Respiratory Distress Syndrome) in Pediatric and Adult

Acute Respiratory Distress Syndrome (ARDS) is a serious medical condition that occurs when lungs become severely inflamed, which inhibits the ability to take in the oxygen and eliminate carbon dioxide. The purpose of this article is to find out more about the clinical manifestation, pathophysiology, diagnosis, and treatment of ARDS. The literatures that used for this literature review are from National Center for Biotechnology Information (NCBI), Google scholar, and Proquest. The result for this literature review is the development of ARDS is associated with inflammation in lung’s epithelium, endothelium, and interstitium which consist three phases which is exudative, proliferative, and fibrotic phases. The Berlin Criteria issued by the American-European Consensus Conference (AECC) in 2021 used for ARDS diagnosis. The treatments for ARDS could used pharmacotherapy and non-pharmacotherapy.

Synergistic Pulmonoprotective Effect of Natural Prolyl Oligopeptidase Inhibitors in In Vitro and In Vivo Models of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a highly morbid inflammatory lung disease with limited pharmacological interventions. The present study aims to evaluate and compare the potential pulmonoprotective effects of natural prolyl oligopeptidase (POP) inhibitors namely rosmarinic acid (RA), chicoric acid (CA), epigallocatechin-3-gallate (EGCG) and gallic acid (GA), against lipopolysaccharide (LPS)-induced ARDS. Cell viability and expression of pro-inflammatory mediators were measured in RAW264.7 cells and in primary murine lung epithelial and bone marrow cells. Nitric oxide (NO) production was also assessed in unstimulated and LPS-stimulated RAW264.7 cells. For subsequent in vivo experiments, the two natural products (NPs) with the most favorable effects, RA and GA, were selected. Protein, cell content and lipid peroxidation levels in bronchoalveolar lavage fluid (BALF), as well as histopathological changes and respiratory parameters were evaluated in LPS-challenged mice. Expression of key mediators involved in ARDS pathophysiology was detected by Western blotting. RA and GA favorably reduced gene expression of pro-inflammatory mediators in vitro, while GA decreased NO production in macrophages. In LPS-challenged mice, RA and GA co-administration improved respiratory parameters, reduced cell and protein content and malondialdehyde (MDA) levels in BALF, decreased vascular cell adhesion molecule-1 (VCAM-1) and the inducible nitric oxide synthase (iNOS) protein expression, activated anti-apoptotic mechanisms and down-regulated POP in the lung. Conclusively, these synergistic pulmonoprotective effects of RA and GA co-administration could render them a promising prophylactic/therapeutic pharmacological intervention against ARDS.

First Stabilize and then Gradually Recruit: A Paradigm Shift in Protective Mechanical Ventilation for Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) is associated with a heterogeneous pattern of injury throughout the lung parenchyma that alters regional alveolar opening and collapse time constants. Such heterogeneity leads to atelectasis and repetitive alveolar collapse and expansion (RACE). The net effect is a progressive loss of lung volume with secondary ventilator-induced lung injury (VILI). Previous concepts of ARDS pathophysiology envisioned a two-compartment system: a small amount of normally aerated lung tissue in the non-dependent regions (termed "baby lung"); and a collapsed and edematous tissue in dependent regions. Based on such compartmentalization, two protective ventilation strategies have been developed: (1) a "protective lung approach" (PLA), designed to reduce overdistension in the remaining aerated compartment using a low tidal volume; and (2) an "open lung approach" (OLA), which first attempts to open the collapsed lung tissue over a short time frame (seconds or minutes) with an initial recruitment maneuver, and then stabilize newly recruited tissue using titrated positive end-expiratory pressure (PEEP). A more recent understanding of ARDS pathophysiology identifies regional alveolar instability and collapse (i.e., hidden micro-atelectasis) in both lung compartments as a primary VILI mechanism. Based on this understanding, we propose an alternative strategy to ventilating the injured lung, which we term a "stabilize lung approach" (SLA). The SLA is designed to immediately stabilize the lung and reduce RACE while gradually reopening collapsed tissue over hours or days. At the core of SLA is time-controlled adaptive ventilation (TCAV), a method to adjust the parameters of the airway pressure release ventilation (APRV) modality. Since the acutely injured lung at any given airway pressure requires more time for alveolar recruitment and less time for alveolar collapse, SLA adjusts inspiratory and expiratory durations and inflation pressure levels. The TCAV method SLA reverses the open first and stabilize second OLA method by: (i) immediately stabilizing lung tissue using a very brief exhalation time (≤0.5 s), so that alveoli simply do not have sufficient time to collapse. The exhalation duration is personalized and adaptive to individual respiratory mechanical properties (i.e., elastic recoil); and (ii) gradually recruiting collapsed lung tissue using an inflate and brake ratchet combined with an extended inspiratory duration (4-6 s) method. Translational animal studies, clinical statistical analysis, and case reports support the use of TCAV as an efficacious lung protective strategy.

Modulation of the Host Response as a Therapeutic Strategy in Severe Lung Infections.

Respiratory pathogens such as influenza and SARS-CoV-2 can cause severe lung infections leading to acute respiratory distress syndrome (ARDS). The pathophysiology of ARDS includes an excessive host immune response, lung epithelial and endothelial cell death and loss of the epithelial and endothelial barrier integrity, culminating in pulmonary oedema and respiratory failure. Traditional approaches for the treatment of respiratory infections include drugs that exert direct anti-pathogen effects (e.g., antivirals). However, such agents are typically ineffective or insufficient after the development of ARDS. Modulation of the host response has emerged as a promising alternative therapeutic approach to mitigate damage to the host for the treatment of respiratory infections; in principle, this strategy should also be less susceptible to the development of pathogen resistance. In this review, we discuss different host-targeting strategies against pathogen-induced ARDS. Developing therapeutics that enhance the host response is a pathogen-agnostic approach that will help prepare for the next pandemic.

Immune cell extravasation in an organ-on-chip to model lung inflammation

Acute respiratory distress syndrome (ARDS) is a severe lung condition with high mortality and various causes, including lung infection. No specific treatment is currently available and more research aimed at better understanding the pathophysiology of ARDS is needed. Most lung-on-chip models that aim at mimicking the air-blood barrier are designed with a horizontal barrier through which immune cells can migrate vertically, making it challenging to visualize and investigate their migration. In addition, these models often lack a barrier of natural protein-derived extracellular matrix (ECM) suitable for live cell imaging to investigate ECM-dependent migration of immune cells as seen in ARDS. This study reports a novel inflammation-on-chip model with live cell imaging of immune cell extravasation and migration during lung inflammation. The three-channel perfusable inflammation-on-chip system mimics the lung endothelial barrier, the ECM environment and the (inflamed) lung epithelial barrier. A chemotactic gradient was established across the ECM hydrogel, leading to the migration of immune cells through the endothelial barrier. We found that immune cell extravasation depends on the presence of an endothelial barrier, on the ECM density and stiffness, and on the flow profile. In particular, bidirectional flow, broadly used in association with rocking platforms, was found to significantly delay extravasation of immune cells in contrast to unidirectional flow. Extravasation was increased in the presence of lung epithelial tissue. This model is currently used to study inflammation-induced immune cell migration but can be used to study infection-induced immune cell migration under different conditions, such as ECM composition, density and stiffness, type of infectious agents used, and the presence of organ-specific cell types.

Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a common and clinically devastating disease that causes respiratory failure. Morbidity and mortality of patients in intensive care units are stubbornly high, and various complications severely affect the quality of life of survivors. The pathophysiology of ARDS includes increased alveolar-capillary membrane permeability, an influx of protein-rich pulmonary edema fluid, and surfactant dysfunction leading to severe hypoxemia. At present, the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema, which primarily improves symptoms, but the prognosis of patients with ARDS is still very poor. Mesenchymal stem cells (MSCs) are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as the umbilical cord, endometrial polyps, menstrual blood, bone marrow, and adipose tissues. Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases. Recently, the potential of stem cells in treating ARDS has been explored via basic research and clinical trials. The efficacy of MSCs has been shown in a variety of in vivo models of ARDS, reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury. This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.

Acute Respiratory Distress Syndrome; A Review of Recent Updates and a Glance into the Future.

Acute respiratory distress syndrome (ARDS) is a rapidly progressive form of respiratory failure that accounts for 10% of admissions to the ICU and is associated with approximately 40% mortality in severe cases. Despite significant mortality and healthcare burden, the mainstay of management remains supportive care. The recent pandemic of SARS-CoV-2 has re-ignited a worldwide interest in exploring the pathophysiology of ARDS, looking for innovative ideas to treat this disease. Recently, many trials have been published utilizing different pharmacotherapy targets; however, the long-term benefits of these agents remain unknown. Metabolomics profiling and stem cell transplantation offer strong enthusiasm and may completely change the outlook of ARDS management in the near future.

Identification of potential biomarkers and therapeutic targets for posttraumatic acute respiratory distress syndrome

BackgroundDespite improved supportive care, posttraumatic acute respiratory distress syndrome (ARDS) mortality has improved very little in recent years. Additionally, ARDS diagnosis is delayed or missed in many patients. We analyzed co-differentially expressed genes (co-DEGs) to explore the relationships between severe trauma and ARDS to reveal potential biomarkers and therapeutic targets for posttraumatic ARDS.MethodsTwo gene expression datasets (GSE64711 and GSE76293) were downloaded from the Gene Expression Omnibus. The GSE64711 dataset included a subset of 244 severely injured trauma patients and 21 healthy controls. GSE76293 specimens were collected from 12 patients with ARDS who were recruited from trauma intensive care units and 11 age- and sex-matched healthy volunteers. Trauma DEGs and ARDS DEGs were identified using the two datasets. Subsequently, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction network analyses were performed to elucidate the molecular functions of the DEGs. Then, hub genes of the co-DEGs were identified. Finally, to explore whether posttraumatic ARDS and septic ARDS are common targets, we included a third dataset (GSE100159) for corresponding verification.Results90 genes were upregulated and 48 genes were downregulated in the two datasets and were therefore named co-DEGs. These co-DEGs were significantly involved in multiple inflammation-, immunity- and neutrophil activation-related biological processes. Ten co-upregulated hub genes (GAPDH, MMP8, HGF, MAPK14, LCN2, CD163, ENO1, CD44, ARG1 and GADD45A) and five co-downregulated hub genes (HERC5, IFIT2, IFIT3, RSAD2 and IFIT1) may be considered potential biomarkers and therapeutic targets for posttraumatic ARDS. Through the verification of the third dataset, posttraumatic ARDS may have its own unique targets worthy of further exploration.ConclusionThis exploratory analysis supports a relationship between trauma and ARDS pathophysiology, specifically in relationship to the identified hub genes. These data may serve as potential biomarkers and therapeutic targets for posttraumatic ARDS.

Pulmonary Thrombosis in Acute Respiratory Distress Syndrome: Theory, Evidence, and Clinical Relevance to Resource-Limited Settings

Thrombosis is often seen in acute respiratory distress syndrome (ARDS) patients, increasing morbidity and mortality. This review highlights the pathophysiology of ARDS and how it links to pulmonary thrombosis. Understanding this link is furthermore critical as pulmonary thrombosis a serious issue in coronavirus diseases, such as COVID-19. There is a clear link between ARDS pathophysiology and pulmonary thrombosis as defined by the “two-path unifying theory” and “two-activation theory of the endothelium”. Interestingly, ARDS in influenza versus COVID-19 patients have a slightly different pathophysiology, the latter having more compact fibrin clots that are more difficult to dissolve; this will impact the treatment of COVID-19 ARDS patients. We therefore also reviewed the current treatment options, underlining that potentially life-saving thrombosis-screening procedures could be lacking in resource-limited settings, therefore needing redress.

Metformin Alleviates LPS-Induced Acute Lung Injury by Regulating the SIRT1/NF-κB/NLRP3 Pathway and Inhibiting Endothelial Cell Pyroptosis.

Acute respiratory distress syndrome (ARDS), a devastating complication of numerous conditions, is often associated with high mortality. It is well known that endothelial cell (EC) damage and inflammation are vital processes in the pathogenesis of ARDS. Nevertheless, the mechanisms of EC damage are largely unknown. In the present study, we investigated the role of pyroptosis in the initiation of ARDS and demonstrated that endothelial pyroptosis might play a pivotal role in the pathophysiology of ARDS. Metformin, an antidiabetic drug, exhibited a protective effect in lipopolysaccharide (LPS)-induced lung injury, and we hypothesized that metformin alleviated LPS-induced lung injury via inhibiting ECs pyroptosis. In vivo, male ICR mice were intratracheally injected with LPS, and metformin was previously administered intraperitoneally. Morphological properties of lung tissues were detected. We showed that metformin inhibited NLRP3 inflammasome activation and NLRP3-stimulated pyroptosis induction, as shown by decreased levels of cleaved caspase-1, N-terminal fragment of GSDMD, and protein contents of IL-1β in lung tissues of mice exposed to LPS. LPS-induced expression of vascular adhesion molecules was also reduced after the treatment with metformin. In vitro, exposure of pulmonary ECs to LPS resulted in increased expression of NLRP3 and pyroptosis-associated indicators. By inhibiting the expression of NLRP3 with NLRP3 inhibitor MCC950, pyroptosis-related markers and vascular adhesion molecules were ameliorated. Moreover, metformin treatment significantly inhibited the NF-κB signaling pathway and increased the expression of sirtuin 1 (SIRT1) both in LPS-stimulated lung tissues and pulmonary ECs. Administration of the selective SIRT1 inhibitor nicotinamide significantly reversed the protective effect of metformin against endothelial pyroptosis and lung injury in LPS-treated ECs and LPS-induced acute lung injury (ALI). Thus, these findings demonstrated that metformin alleviated LPS-induced ALI by inhibiting NF-κB-NLRP3–mediated ECs pyroptosis, possibly by upregulating the expression of SIRT1.