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Background: By controlling hypercapnia, respiratory acidosis, and associated consequences, extracorporeal CO2 removal (ECCO2R) has the potential to facilitate ultra-protective lung ventilation (UPLV) strategies and to decrease injury from mechanical ventilation. We convened a meeting of European intensivists and nephrologists and used a modified Delphi process to provide updated insights into the role of ECCO2R in acute respiratory distress syndrome (ARDS) and to identify recommendations for a future randomized controlled trial. Results: The group agreed that lung protective ventilation and UPLV should have distinct definitions, with UPLV primarily defined by a tidal volume (VT) of 4–6 mL/kg predicted body weight with a driving pressure (ΔP) ≤ 14–15 cmH2O. Fourteen (93%) participants agreed that ECCO2R would be needed in the majority of patients to implement UPLV. Furthermore, 10 participants (majority, 63%) would select patients with PaO2:FiO2 > 100 mmHg (> 13.3 kPa) and 14 (consensus, 88%) would select patients with a ventilatory ratio of > 2.5–3. A minimum CO2 removal rate of 80 mL/min delivered by continuous renal support machines was suggested (11/14 participants, 79%) for this objective, using a short, double-lumen catheter inserted into the right internal jugular vein as the preferred vascular access. Of the participants, 14/15 (93%, consensus) stated that a new randomized trial of ECCO2R is needed in patients with ARDS. A ΔP of ≥ 14–15 cmH2O was suggested by 12/14 participants (86%) as the primary inclusion criterion. Conclusions: ECCO2R may facilitate UPLV with lower volume and pressures provided by the ventilator, while controlling respiratory acidosis. Since recent European Society of Intensive Care Medicine guidelines on ARDS recommended against the use of ECCO2R for the treatment of ARDS outside of randomized controlled trials, new trials of ECCO2R are urgently needed, with a ΔP of ≥ 14–15 cmH2O suggested as the primary inclusion criterion. [ABSTRACT FROM AUTHOR]

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in type 2 alveolar epithelial (AT2) cells is thought to aggravate alveolar inflammation in acute lung injury. Here, the authors show that the mtLCFAO rate limiting enzyme CPT1a is decreased in AT2 cells in acute respiratory distress syndrome, highlighting the role of mtLCFAO in immunometabolism in this context. [ABSTRACT FROM AUTHOR]

Background: Severe bacterial infections can trigger acute lung injury (ALI) and acute respiratory distress syndrome, with bacterial pathogen‐associated molecular patterns (PAMPs) exacerbating the inflammatory response, particularly in COVID‐19 patients. Cyclic‐di‐GMP (CDG), one of the PAMPs, is synthesized by various Gram‐positve and Gram‐negative bacteria. Previous studies mainly focused on the inflammatory responses triggered by intracellular bacteria‐released CDG. However, how extracellular CDG, which is released by bacterial autolysis or rupture, activates the inflammatory response remains unclear. Methods: The interaction between extracellular CDG and myeloid differentiation protein 2 (MD2) was investigated using in vivo and in vitro models. MD2 blockade was achieved using specific inhibitor and genetic knockout mice. Site‐directed mutagenesis, co‐immunoprecipitation, SPR and Bis‐ANS displacement assays were used to identify the potential binding sites of MD2 on CDG. Results: Our data show that extracellular CDG directly interacts with MD2, leading to activation of the TLR4 signalling pathway and lung injury. Specific inhibitors or genetic knockout of MD2 in mice significantly alleviated CDG‐induced lung injury. Moreover, isoleucine residues at positions 80 and 94, along with phenylalanine at position 121, are essential for the binding of MD2 to CDG. Conclusion: These results reveal that extracellular CDG induces lung injury through direct interaction with MD2 and activation of the TLR4 signalling pathway, providing valuable insights into bacteria‐induced ALI mechanisms and new therapeutic approaches for the treatment of bacterial co‐infection in COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Given the important role of patient-ventilator assessments in ensuring the safety and efficacy of mechanical ventilation, a team of respiratory therapists and a librarian used Grading of Recommendations, Assessment, Development, and Evaluation methodology to make the following recommendations: (1) We recommend assessment of plateau pressure to ensure lung-protective ventilator settings (strong recommendation, high certainty); (2) We recommend an assessment of tidal volume (VT) to ensure lung-protective ventilation (4-8 mL/kg/predicted body weight) (strong recommendation, high certainty); (3) We recommend documenting VT as mL/kg predicted body weight (strong recommendation, high certainty); (4) We recommend an assessment of PEEP and auto-PEEP (strong recommendation, high certainty); (5) We suggest assessing driving pressure to prevent ventilator-induced injury (conditional recommendation, low certainty); (6) We suggest assessing FIO2 to ensure normoxemia (conditional recommendation, very low certainty); (7) We suggest telemonitoring to supplement direct bedside assessment in settings with limited resources (conditional recommendation, low certainty); (8) We suggest direct bedside assessment rather than telemonitoring when resources are adequate (conditional recommendation, low certainty); (9) We suggest assessing adequate humidification for patients receiving noninvasive ventilation (NIV) and invasive mechanical ventilation (conditional recommendation, very low certainty); (10) We suggest assessing the appropriateness of the humidification device during NIV and invasive mechanical ventilation (conditional recommendation, low certainty); (11) We recommend that the skin surrounding artificial airways and NIV interfaces be assessed (strong recommendation, high certainty); (12) We suggest assessing the dressing used for tracheostomy tubes and NIV interfaces (conditional recommendation, low certainty); (13) We recommend assessing the pressure inside the cuff of artificial airways using a manometer (strong recommendation, high certainty); (14) We recommend that continuous cuff pressure assessment should not be implemented to decrease the risk of ventilator-associated pneumonia (strong recommendation, high certainty); and (15) We suggest assessing the proper placement and securement of artificial airways (conditional recommendation, very low certainty). [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, acute lung injury (ALI) and ARDS have emerged as critical health concerns, drawing considerable attention from clinicians. The volume of published articles on ALI/ARDS is on the rise, indicating the expanding research interest in this field. However, the precise quantity and quality of studies on ALI/ARDS remain unclear. Consequently, we employed bibliometric and visual techniques to comprehensively analyze the patterns and focal points of these articles. METHODS: To investigate the characteristics of highly referenced papers on ALI/ARDS and offer insights into the progress and advancements in research on ALI/ARDS, we conducted a comprehensive search in the core Web of Science database for cited articles using the terms "ALI," "acute lung injury," "ARDS," or "acute respiratory distress syndrome." A total of 60,282 citations were retrieved by narrowing the scope to reviews, articles, and publications in English. From the obtained citations, we selected materials for analysis from the top 100 articles with the highest number of citations. Subsequently, the articles were visualized and analyzed using VOSviewer, CiteSpace, and bibliometric techniques. This analysis focused on identifying trends related to authors, journals, countries, institutions, collaborative networks, key words, and other relevant factors in the field of ALI/ARDS research. RESULTS: Among the top 100 cited articles, the highest and lowest number of citations were 6,957 and 451, respectively. The 100 articles were published between 1991-2020, with a peak in publications observed in 2004, 2005, and 2012 (no. = 7). Among 29 journals, The New England Journal of Medicine (no. = 21) had the highest number of publications, followed by the American Journal of Respiratory and Critical Care Medicine (no. = 14). Among the 29 countries represented in the top 100 cited articles, the United States (no. = 51) emerged as the leading country in the number of publications, followed by Canada (no. = 19) (there was some overlap in paper output between countries due to co-publication). The 3 predominant keywords identified in studies within the ALI/ARDS domain were ALI, mechanical ventilation, and PEEP. CONCLUSIONS: This study provides a historical perspective on the scientific advancements in ALI/ARDS research, highlighting the need for further investigation and development in specific areas within the field. Bibliometric analyses revealed that the United States is the predominant force in the field of ALI/ARDS, contributing significantly to its development. Through an examination of highly cited papers on ALI/ARDS, we have identified global research trends, assessed the quality of studies, and identified hot topics in the field of ALI/ARDS. [ABSTRACT FROM AUTHOR]

Adult rats exposed to hyperoxia (>95% O2) die from respiratory failure in 60–72 h. However, rats preconditioned with >95% O2 for 48 h followed by 24 h in room air acquire tolerance of hyperoxia (H-T), whereas rats preconditioned with 60% O2 for 7 days become more susceptible (H-S). Our objective was to evaluate lung tissue mitochondrial bioenergetics in H-T and H-S rats. Bioenergetics was assessed in mitochondria isolated from lung tissue of H-T, H-S, and control rats. Expressions of complexes involved in oxidative phosphorylation (OxPhos) were measured in lung tissue homogenate. Pulmonary endothelial filtration coefficient (Kf) and tissue mitochondrial membrane potential (Δψm) were evaluated in isolated perfused lungs (IPLs). Results show that ADP-induced state 3 OxPhos capacity (Vmax) decreased in H-S mitochondria but increased in H-T. Δψm repolarization time following ADP-stimulated depolarization increased in H-S mitochondria. Complex I expression decreased in H-T (38%) and H-S (43%) lung homogenate, whereas complex V expression increased (70%) in H-T lung homogenate. Δψm is unchanged in H-S and H-T lungs, but complex II has a larger contribution to Δψm in H-S than H-T lungs. Kf increased in H-S, but not in H-T lungs. For H-T, increased complex V expression and Vmax counter the effect of the decrease in complex I expression on Δψm. A larger complex II contribution to Δψm along with decreased Vmax and increased Kf could make H-S rats more hyperoxia susceptible. Results are clinically relevant since ventilation with ≥60% O2 is often required for extended periods in patients with acute respiratory distress syndrome (ARDS). NEW & NOTEWORTHY: We assessed lung tissue mitochondrial bioenergetics in rats with tolerance (H-T) or susceptibility (H-S) to hyperoxia-induced ARDS. Results from studies in isolated mitochondria, tissue homogenate, and isolated perfused lungs show that mitochondrial bioenergetics are differentially altered in H-T and H-S lungs suggesting a potential role for mitochondrial bioenergetics in hyperoxia-induced ARDS. Results are clinically relevant since hyperoxia exposure is a primary therapy for patients with ARDS, and differential sensitivity to hyperoxia surely occurs in humans. [ABSTRACT FROM AUTHOR]

Patient self-inflicted lung injury (P-SILI) is a major challenge for the ICU physician: although spontaneous breathing is associated with physiological benefits, in patients with acute respiratory distress syndrome (ARDS), the risk of uncontrolled inspiratory effort leading to additional injury needs to be assessed to avoid delayed intubation and increased mortality. In the present review, we analyze the available clinical and experimental evidence supporting the existence of lung injury caused by uncontrolled high inspiratory effort, we discuss the pathophysiological mechanisms by which increased effort causes P-SILI, and, finally, we consider the measurements and interpretation of bedside physiological measures of increased drive that should alert the clinician. The data presented in this review could help to recognize injurious respiratory patterns that may trigger P-SILI and to prevent it. [ABSTRACT FROM AUTHOR]

Background: The recruitment-to-inflation ratio (R/I) has been recently proposed to bedside assess response to PEEP. The impact of PEEP on ventilator-induced lung injury depends on the extent of dynamic strain reduction. We hypothesized that R/I may reflect the potential for lung recruitment (i.e. recruitability) and, consequently, estimate the impact of PEEP on dynamic lung strain, both assessed through computed tomography scan. Methods: Fourteen lung-damaged pigs (lipopolysaccharide infusion) underwent ventilation at low (5 cmH2O) and high PEEP (i.e., PEEP generating a plateau pressure of 28–30 cmH2O). R/I was measured through a one-breath derecruitment maneuver from high to low PEEP. PEEP-induced changes in dynamic lung strain, difference in nonaerated lung tissue weight (tissue recruitment) and amount of gas entering previously nonaerated lung units (gas recruitment) were assessed through computed tomography scan. Tissue and gas recruitment were normalized to the weight and gas volume of previously ventilated lung areas at low PEEP (normalized-tissue recruitment and normalized-gas recruitment, respectively). Results: Between high (median [interquartile range] 20 cmH2O [18–21]) and low PEEP, median R/I was 1.08 [0.88–1.82], indicating high lung recruitability. Compared to low PEEP, tissue and gas recruitment at high PEEP were 246 g [182–288] and 385 ml [318–668], respectively. R/I was linearly related to normalized-gas recruitment (r = 0.90; [95% CI 0.71 to 0.97) and normalized-tissue recruitment (r = 0.69; [95% CI 0.25 to 0.89]). Dynamic lung strain was 0.37 [0.29–0.44] at high PEEP and 0.59 [0.46–0.80] at low PEEP (p < 0.001). R/I was significantly related to PEEP-induced reduction in dynamic (r = − 0.93; [95% CI − 0.78 to − 0.98]) and global lung strain (r = − 0.57; [95% CI − 0.05 to − 0.84]). No correlation was found between R/I and and PEEP-induced changes in static lung strain (r = 0.34; [95% CI − 0.23 to 0.74]). Conclusions: In a highly recruitable ARDS model, R/I reflects the potential for lung recruitment and well estimates the extent of PEEP-induced reduction in dynamic lung strain. [ABSTRACT FROM AUTHOR]

Immune activation is essential for lung control of viral and bacterial infection, but an overwhelming inflammatory response often leads to the onset of acute respiratory distress syndrome. IL-10 plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the present study, we investigated the role of IL-10 in acute lung injury induced by influenza A virus and methicillin-resistant Staphylococcus aureus coinfection. This unique coinfection model resembles patients with acute pneumonia undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor gene-deficient mice, as well as in vivo neutralizing antibodies, we show that IL-10 deficiency promotes IFN-γ–dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-γ neutralization during coinfection. Further studies using mice with Il10ra deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-γ/TNF-α hyperproduction and acute mortality. Importantly, this antiinflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and acute respiratory distress syndrome pathogenesis by counteracting the IFN-γ response. [ABSTRACT FROM AUTHOR]

The lung is an important site of extramedullary platelet formation, and megakaryocytes in the lung participate in immune responses in addition to platelet production. In acute lung injury and chronic lung injury, megakaryocytes and platelets play a promoting or protective role through different mechanisms. The authors reviewed the role of megakaryocytes and platelets in common clinical lung injuries with different course of disease and different pathogenic factors in order to provide new thinking for the diagnosis and treatment of lung injuries. [ABSTRACT FROM AUTHOR]

Objective: To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL). Methods: A rat model for ALI/acute respiratory distress syndrome (ALI/ARDS) was established. Pathological examination of lung tissue was conducted to assess lung injury. Blood gas in the arteries was measured using a blood analyzer. Changes in PaO2, PaO2/FiO2, and lung wet/dry (W/D) weight ratio were carefully compared. ELISA assay was conducted to estimate cell adhesion and inflammation response. Finally, real-time reverse transcription polymerase chain reaction and western blotting assay was used to determine the activation of PI3K/AKT/mTOR pathway. Results: ARDS in vivo model was successfully constructed by LPS injection. Compared with the sham group, PaO2 and PaO2/FiO2 were significantly lower in the vehicle group, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8 andTNF-αwere significantly increased. After treatment with different doses of sivelestat sodium, we found PaO2, PaO2/FiO2 were prominently increased, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8, TNF-α levels were decreased in the dose-dependent manner. Meanwhile, compared with the vehicle group, the expression levels of Bax, PI3K, Akt and mTOR were significantly lower, and the expression of Bcl-2 was significantly higher after injection with sivelestat sodium. Conclusion: Sivelestat sodium has an interventional effect on ALI in sepsis by inhibiting the PI3K/AKT/mTOR signalling pathway. [ABSTRACT FROM AUTHOR]

The article focuses on investigating whether electrical impedance tomography (EIT) can detect the onset and progression of ventilator-induced lung injury (VILI) in an animal model of VILI. It is reported that the study involved a retrospective analysis of healthy female domestic pigs ventilated for 48 hours, aiming to assess changes in lung electrical impedance compared to other parameters such as oxygenation, respiratory mechanics, and lung pathology.

Background: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery. Methods: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (CRS < 0.6 (mL/Kg)/cmH2O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score (mLIS), a composite measure that integrated daily measurements of CRS, along with oxygen requirements, oxygenation, and X-rays up to day 28. The mLIS score was also hierarchically adjusted for survival and extubation rates. Results: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average mLIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the mLIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in CRS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups. Conclusions: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020. [ABSTRACT FROM AUTHOR]

Purpose: Patients with hyper- vs. hypo-inflammatory subphenotypes of acute respiratory distress syndrome (ARDS) exhibit different clinical outcomes. Inflammation increases the production of reactive oxygen species (ROS) and increased ROS contributes to the severity of illness. Our long-term goal is to develop electron paramagnetic resonance (EPR) imaging of lungs in vivo to precisely measure superoxide production in ARDS in real time. As a first step, this requires the development of in vivo EPR methods for quantifying superoxide generation in the lung during injury, and testing if such superoxide measurements can differentiate between susceptible and protected mouse strains. Procedures: In WT mice, mice lacking total body extracellular superoxide dismutase (EC-SOD) (KO), or mice overexpressing lung EC-SOD (Tg), lung injury was induced with intraperitoneal (IP) lipopolysaccharide (LPS) (10 mg/kg). At 24 h after LPS treatment, mice were injected with the cyclic hydroxylamines 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine hydrochloride (CPH) or 4-acetoxymethoxycarbonyl-1-hydroxy-2,2,5,5-tetramethylpyrrolidine-3-carboxylic acid (DCP-AM-H) probes to detect, respectively, cellular and mitochondrial ROS – specifically superoxide. Several probe delivery strategies were tested. Lung tissue was collected up to one hour after probe administration and assayed by EPR. Results: As measured by X-band EPR, cellular and mitochondrial superoxide increased in the lungs of LPS-treated mice compared to control. Lung cellular superoxide was increased in EC-SOD KO mice and decreased in EC-SOD Tg mice compared to WT. We also validated an intratracheal (IT) delivery method, which enhanced the lung signal for both spin probes compared to IP administration. Conclusions: We have developed protocols for delivering EPR spin probes in vivo, allowing detection of cellular and mitochondrial superoxide in lung injury by EPR. Superoxide measurements by EPR could differentiate mice with and without lung injury, as well as mouse strains with different disease susceptibilities. We expect these protocols to capture real-time superoxide production and enable evaluation of lung EPR imaging as a potential clinical tool for subphenotyping ARDS patients based on redox status. [ABSTRACT FROM AUTHOR]

Background: ALI/ARDS is a syndrome of acute onset characterized by progressive hypoxemia and noncardiogenic pulmonary edema as the primary clinical manifestations. Necroptosis is a form of programmed cell necrosis that is precisely regulated by molecular signals. This process is characterized by organelle swelling and membrane rupture, is highly immunogenic, involves extensive crosstalk with various cellular stress mechanisms, and is significantly implicated in the onset and progression of ALI/ARDS. Methods: The current body of literature on necroptosis and ALI/ARDS was thoroughly reviewed. Initially, an overview of the molecular mechanism of necroptosis was provided, followed by an examination of its interactions with apoptosis, pyroptosis, autophagy, ferroptosis, PANOptosis, and NETosis. Subsequently, the involvement of necroptosis in various stages of ALI/ARDS progression was delineated. Lastly, drugs targeting necroptosis, biomarkers, and current obstacles were presented. Conclusion: Necroptosis plays an important role in the progression of ALI/ARDS. However, since ALI/ARDS is a clinical syndrome caused by a variety of mechanisms, we emphasize that while focusing on necroptosis, it may be more beneficial to treat ALI/ARDS by collaborating with other mechanisms. [ABSTRACT FROM AUTHOR]

Chronic cigarette smoke exposure decreases lung expression of WWOX which is known to protect the endothelial barrier during infectious models of acute respiratory distress syndrome (ARDS). Proteomic analysis of WWOX-silenced endothelial cells (ECs) was done using tandem mass tag mass spectrometry (TMT-MS). WWOX-silenced ECs as well as those isolated from endothelial cell Wwox knockout (EC Wwox KO) mice were subjected to cyclic stretch (18% elongation, 0.5 Hz, 4 h). Cellular lysates and media supernatant were harvested for assays of cellular signaling, protein expression, and cytokine release. These were repeated with dual silencing of WWOX and zyxin. Control and EC Wwox KO mice were subjected to high tidal volume ventilation. Bronchoalveolar lavage fluid and mouse lung tissue were harvested for cellular signaling, cytokine secretion, and histological assays. TMT-MS revealed upregulation of zyxin expression during WWOX knockdown which predicted a heightened inflammatory response to mechanical stretch. WWOX-silenced ECs and ECs isolated from EC Wwox mice displayed significantly increased cyclic stretch-mediated secretion of various cytokines (IL-6, KC/IL-8, IL-1β, and MCP-1) relative to controls. This was associated with increased ERK and JNK phosphorylation but decreased p38 mitogen-activated kinases (MAPK) phosphorylation. EC Wwox KO mice subjected to VILI sustained a greater degree of injury than corresponding controls. Silencing of zyxin during WWOX knockdown abrogated stretch-induced increases in IL-8 secretion but not in IL-6. Loss of WWOX function in ECs is associated with a heightened inflammatory response during mechanical stretch that is associated with increased MAPK phosphorylation and appears, in part, to be dependent on the upregulation of zyxin. NEW & NOTEWORTHY Prior tobacco smoke exposure is associated with an increased risk of acute respiratory distress syndrome (ARDS) during critical illness. Our laboratory is investigating one of the gene expression changes that occurs in the lung following smoke exposure: WWOX downregulation. Here we describe changes in protein expression associated with WWOX knockdown and its influence on ventilator-induced ARDS in a mouse model. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) manifests through harm to the capillary endothelium and alveolar epithelial cells, arising from a multitude of factors, leading to scattered interstitial alterations, pulmonary edema, and subsequent acute hypoxic respiratory insufficiency. Acute lung injury (ALI), along with its more serious counterpart, acute respiratory distress syndrome (ARDS), carry a fatality rate that hovers around 30– 40%. Its principal pathological characteristic lies in the unchecked inflammatory reaction. Currently, the main strategies for treating ALI are alleviation of inflammation and prevention of respiratory failure. Concerning the etiology of ALI, NLRP3 Inflammasome is essential to the body's innate immune response. The composition of this inflammasome complex includes NLRP3, the pyroptosis mediator ASC, and pro-caspase-1. Recent research has reported that the inflammatory response centered on NLRP3 inflammasomes plays a key part in inflammation in ALI, and may hence be a prospective candidate for therapeutic intervention. In the review, we present an overview of the ailment characteristics of acute lung injury along with the constitution and operation of the NLRP3 inflammasome within this framework. We also explore therapeutic strategies targeting the NLRP3 inflammasome to combat acute lung injury. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is characterized by alveolar edema that can progress to septal fibrosis. Mechanical ventilation can augment lung injury, termed ventilator-induced lung injury (VILI). Connective tissue growth factor (CTGF), a mediator of fibrosis, is increased in ARDS patients. Blocking CTGF inhibits fibrosis and possibly vascular leakage. This study investigated whether neutralizing CTGF reduces pulmonary edema in VILI. Methods: Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low VT) or moderate (10 mL/kg; mod VT) tidal volume and treated with a neutralizing CTGF antibody (FG-3154) or placebo lgG (vehicle). Control rats without LPS were ventilated for 6 h with low VT. Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined. Results: VILI was characterized by reduced PaO2/FiO2 ratio (low VT: 540 [381–661] vs. control: 693 [620–754], p < 0.05), increased wet-to-dry weight ratio (low VT: 4.8 [4.6–4.9] vs. control: 4.5 [4.4–4.6], p < 0.05), pneumonia (low VT: 30 [0–58] vs. control: 0 [0–0]%, p < 0.05) and interstitial inflammation (low VT: 2 [1–3] vs. control: 1 [0–1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod VT + FG-3154: 4.8 [4.7–5.0] vs. mod VT + vehicle: 4.8 [4.8–5.0], p > 0.99), extravasated dextrans (mod VT + FG-3154: 0.06 [0.04–0.09] vs. mod VT + vehicle: 0.04 [0.03–0.09] µg/mg tissue, p > 0.99), sRAGE (mod VT + FG-3154: 1865 [1628–2252] vs. mod VT + vehicle: 1885 [1695–2159] pg/mL, p > 0.99) or histopathology. Conclusions: 'Double hit' VILI was characterized by inflammation, impaired oxygenation, pulmonary edema and histopathological lung injury. Blocking CTGF does not improve oxygenation nor reduce pulmonary edema in rats with VILI. [ABSTRACT FROM AUTHOR]

Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFβ signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to Bcell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. Conclusion: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study sought to develop noninvasive, in vivo imaging schemes that allow for quantitative assessment of pulmonary microvascular functional status based on the combination of pulmonary T1 mapping and dynamic contrast‐enhanced (DynCE) imaging. Ultrashort‐echo‐time (UTE) imaging at 9.4 T of lung parenchyma was performed. Retrospective gating was based on modulation of the first point in each recorded spoke. T1 maps were obtained using a series of five consecutive images with varying RF angles and analyzed with the variable flip angle approach. The obtained mean T1 lung value of 1078 ± 38 ms correlated well with previous reports. Improved intersession variability was observed, as evident from a decreased standard deviation of motion‐resolved T1 mapping (F‐test = 0.051). Animals received lipopolysaccharide (LPS) and were imaged at t = 2, 6, and 12 h after administration. The nitric oxide (NO)‐dependent function was assessed according to changes in lung T1 after L‐NAME injection, while microvascular perfusion and oxidant stress were assessed with contrast‐enhanced imaging after injection of gadolinium or 3‐carbamoyl‐proxyl nitroxide radical, respectively. Retrospectivel gated UTE allowed robust, motion‐compensated imaging that could be used for T1 mapping of lung parenchyma. Changes in lung T1 after L‐NAME injection indicated that LPS induced overproduction of NO at t = 2 and 6 h after LPS, but NO‐dependent microvascular function was impaired at t = 12 h after LPS. DynCE imaging at t = 6 h after LPS injection revealed decreased microvascular perfusion, with increased vascular permeability and oxidant stress. MRI allows to visualize and quantify lung microvascular NO‐dependent function and its concomitant impairment during acute respiratory distress syndrome development with high sensitivity. UTE T1 mapping appears to be sensitive and useful in probing pulmonary microvascular functional status. [ABSTRACT FROM AUTHOR]

Sepsis, a prevalent critical condition in clinics, continues to be the leading cause of death from infections and a global healthcare issue. Among the organs susceptible to the harmful effects of sepsis, the lungs are notably the most frequently affected. Consequently, patients with sepsis are predisposed to developing acute lung injury (ALI), and in severe cases, acute respiratory distress syndrome (ARDS). Nevertheless, the precise mechanisms associated with the onset of ALI/ARDS remain elusive. In recent years, there has been a growing emphasis on the role of endothelial cells (ECs), a cell type integral to lung barrier function, and their interactions with various stromal cells in sepsis-induced ALI/ARDS. In this comprehensive review, we summarize the involvement of endothelial cells and their intricate interplay with immune cells and stromal cells, including pulmonary epithelial cells and fibroblasts, in the pathogenesis of sepsis-induced ALI/ARDS, with particular emphasis placed on discussing the several pivotal pathways implicated in this process. Furthermore, we discuss the potential therapeutic interventions for modulating the functions of endothelial cells, their interactions with immune cells and stromal cells, and relevant pathways associated with ALI/ARDS to present a potential therapeutic strategy for managing sepsis and sepsis-induced ALI/ARDS. [ABSTRACT FROM AUTHOR]

Highlights: LPS-induced ARDS rats and PMVECs have low Fcgr2b level and high Elk1 level; Fcgr2b overexpression mitigates LPS-induced ALI/ARDS in rats and PMVECs; Elk1 knockdown mitigates LPS-induced ALI/ARDS in rats and PMVECs; Elk1 represses Fcgr2b transcription by recruiting H3K9me3; Elk1/Fcgr2b axis aggravates LPS-induced ALI/ARDS in rats and PMVECs. Objective: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with significant mortality rates. The role of Fcgr2b in the pathogenesis of ALI/ARDS is not fully elucidated. This study aimed to investigate the functions of Fcgr2b in ALI/ARDS and explore its underlying mechanisms. Methods: Methods: In this study, rat models of ARDS and pulmonary microvascular endothelial cell (PMVEC) injury models were established through the administration of lipopolysaccharide (LPS). The expression levels of Fcgr2b and Elk1 were quantified in both LPS-induced ARDS rats and PMVECs. Subsequent gain- and loss-of-function experiments were conducted, followed by comprehensive assessments of lung tissue for pathomorphological changes, edema, glycogen storage, fibrosis, and infiltration of inflammatory cells. Additionally, bronchoalveolar lavage fluid was analyzed for T-helper 17 (Th17) cell infiltration, inflammatory response, and microvascular permeability to evaluate lung injury severity in ARDS models. Furthermore, the activity, cytotoxicity, apoptosis, and angiogenic potential of PMVECs were assessed to gauge cell injury. The interaction between Elk1 and Fcgr2b was also examined to confirm their regulatory relationship. Results: In the context of LPS-induced ARDS and PMVEC injury, Fcgr2b expression was markedly reduced, whereas Elk1 expression was elevated. Overexpression of Fcgr2b led to a decrease in Th17 cell infiltration and mitigated lung tissue damage in ARDS models, in addition to reducing LPS-induced injury in PMVECs. Elk1 was found to suppress Fcgr2b transcription through the recruitment of histone 3 lysine 9 trimethylation (H3K9me3). Knockdown of Elk1 diminished Th17 cell infiltration and lung tissue damage in ARDS models, and alleviated LPS-induced injury in PMVECs, effects that were reversed upon Fcgr2b upregulation. Conclusion: Elk1 negatively regulates Fcgr2b transcription, thereby augmenting the inflammatory response and exacerbating lung injury in LPS-induced ALI/ARDS. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients, and diffuse alveolar damage (DAD) is considered its histological hallmark. Sepsis is one of the most common aetiology of ARDS with the highest case-fatality rate. Identifying ARDS patients and differentiate them from other causes of acute respiratory failure remains a challenge. To address this, many studies have focused on identifying biomarkers that can help assess lung epithelial injury. However, there is scarce information available regarding the tissue expression of these markers. Evaluating the expression of elafin, RAGE, and SP-D in lung tissue offers a potential bridge between serological markers and the underlying histopathological changes. Therefore, we hypothesize that the expression of epithelial injury markers varies between sepsis and ARDS as well as according to its severity. Methods: We compared the post-mortem lung tissue expression of the epithelial injury markers RAGE, SP-D, and elafin of patients that died of sepsis, ARDS, and controls that died from non-pulmonary causes. Lung tissue was collected during routine autopsy and protein expression was assessed by immunohistochemistry. We also assessed the lung injury by a semi-quantitative analysis. Results: We observed that all features of DAD were milder in septic group compared to ARDS group. Elafin tissue expression was increased and SP-D was decreased in the sepsis and ARDS groups. Severe ARDS expressed higher levels of elafin and RAGE, and they were negatively correlated with PaO2/FiO2 ratio, and positively correlated with bronchopneumonia percentage and hyaline membrane score. RAGE tissue expression was negatively correlated with mechanical ventilation duration in both ARDS and septic groups. In septic patients, elafin was positively correlated with ICU admission length, SP-D was positively correlated with serum lactate and RAGE was correlated with C-reactive protein. Conclusions: Lung tissue expression of elafin and RAGE, but not SP-D, is associated with ARDS severity, but does not discriminate sepsis patients from ARDS patients. [ABSTRACT FROM AUTHOR]

Nanoparticles have attracted extensive attention due to their high degree of cell targeting, biocompatibility, controllable biological activity, and outstanding pharmacokinetics. Changing the size, morphology, and surface chemical groups of nanoparticles can increase the biological distribution of agents to achieve precise tissue targeting and optimize therapeutic effects. Examples of their use include nanoparticles designed for increasing antigen-specific immune responses, developing vaccines, and treating inflammatory diseases. Nanoparticles show the potential to become a new generation of therapeutic agents for regulating inflammation. Recently, many nanomaterials with targeted properties have been developed to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In this review, we provide a brief explanation of the pathological mechanism underlying ALI/ARDS and a systematic overview of the latest technology and research progress in nanomedicine treatments of ALI, including improved nanocarriers, nanozymes, and nanovaccines for the targeted treatment of lung injury. Ultimately, these nanomedicines will be used for the clinical treatment of ALI/ARDS. [ABSTRACT FROM AUTHOR]

During veno-venous extracorporeal membrane oxygenation (V-V ECMO), blood is drained from the central venous circulation to be oxygenated and decarbonated by an artificial lung. It is then reinfused into the right heart and pulmonary circulation where further gas-exchange occurs. Each of these steps is characterized by a peculiar physiology that this manuscript analyses, with the aim of providing bedside tools for clinical care: we begin by describing the factors that affect the efficiency of blood drainage, such as patient and cannulae position, fluid status, cardiac output and ventilatory strategies. We then dig into the complexity of extracorporeal gas-exchange, with particular reference to the effects of extracorporeal blood-flow (ECBF), fraction of delivered oxygen (FdO2) and sweep gas-flow (SGF) on oxygenation and decarbonation. Subsequently, we focus on the reinfusion of arterialized blood into the right heart, highlighting the effects on recirculation and, more importantly, on right ventricular function. The importance and challenges of haemodynamic monitoring during V-V ECMO are also analysed. Finally, we detail the interdependence between extracorporeal circulation, native lung function and mechanical ventilation in providing adequate arterial blood gases while allowing lung rest. In the absence of evidence-based strategies to care for this particular group of patients, clinical practice is underpinned by a sound knowledge of the intricate physiology of V-V ECMO. [ABSTRACT FROM AUTHOR]

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterised by an uncontrolled inflammatory response, and current treatment strategies have limited efficacy. Although the protective effect of M2‐like macrophages (M2φ) and their extracellular vesicles (EVs) has been well‐documented in other inflammatory diseases, the role of M2φ‐derived EVs (M2φ‐EVs) in the pathogenesis of ALI/ARDS remains poorly understood. The present study utilised a mouse model of lipopolysaccharide‐induced ALI to first demonstrate a decrease in endogenous M2‐like alveolar macrophage‐derived EVs. And then, intratracheal instillation of exogenous M2φ‐EVs from the mouse alveolar macrophage cell line (MH‐S) primarily led to a take up by alveolar macrophages, resulting in reduced lung inflammation and injury. Mechanistically, the M2φ‐EVs effectively suppressed the pyroptosis of alveolar macrophages and inhibited the release of excessive cytokines such as IL‐6, TNF‐α and IL‐1β both in vivo and in vitro, which were closely related to NF‐κB/NLRP3 signalling pathway inhibition. Of note, the protective effect of M2φ‐EVs was partly mediated by miR‐709, as evidenced by the inhibition of miR‐709 expression in M2φ‐EVs mitigated their protective effect against lipopolysaccharide‐induced ALI in mice. In addition, we found that the expression of miR‐709 in EVs derived from bronchoalveolar lavage fluid was correlated negatively with disease severity in ARDS patients, indicating its potential as a marker for ARDS severity. Altogether, our study revealed that M2φ‐EVs played a protective role in the pathogenesis of ALI/ARDS, partly mediated by miR‐709, offering a potential strategy for assessing disease severity and treating ALI/ARDS. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are characterized by uncontrolled inflammatory responses, neutrophil activation and infiltration, damage to the alveolar capillary membrane, and diffuse alveolar injury. Neutrophil extracellular traps (NETs), formed by activated neutrophils, contribute significantly to various inflammatory disorders and can lead to tissue damage and organ dysfunction. Corilagin, a compound found in Phyllanthus urinaria, possesses antioxidative and anti-inflammatory properties. In this study, we investigated the protective effects and underlying mechanisms of corilagin in hydrochloric acid (HCl)/lipopolysaccharide (LPS)-induced lung injury. Mice received intraperitoneal administration of corilagin (2.5, 5, or 10 mg/kg) or an equal volume of saline 30 min after intratracheal HCl/LPS administration. After 20 h, lung tissues were collected for analysis. Corilagin treatment significantly mitigated lung injury, as evidenced by reduced inflammatory cell infiltration, decreased production of proinflammatory cytokines, and alleviated oxidative stress. Furthermore, corilagin treatment suppressed neutrophil elastase expression, reduced NET formation, and inhibited the expression of ERK, p38, AKT, STAT3, and NOX2. Our findings suggest that corilagin inhibits NET formation and protects against HCl/LPS-induced ALI in mice by modulating the STAT3 and NOX2 signaling pathways. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality but lacks specific therapeutic options. Diverse endocytic processes play a key role in all phases of acute lung injury (ALI), including the initial insult, development of respiratory failure due to alveolar flooding, as a consequence of altered alveolar-capillary barrier function, as well as in the resolution or deleterious remodeling after injury. In particular, clathrin-, caveolae-, endophilin- and glycosylphosphatidyl inositol-anchored protein-mediated endocytosis, as well as, macropinocytosis and phagocytosis have been implicated in the setting of acute lung damage. This manuscript reviews our current understanding of these endocytic pathways and subsequent intracellular trafficking in various phases of ALI, and also aims to identify potential therapeutic targets for patients with ARDS. [ABSTRACT FROM AUTHOR]

Background: With the increasing research on extracellular vesicles (EVs), EVs have received widespread attention as biodiagnostic markers and therapeutic agents for a variety of diseases. Stem cell-derived EVs have also been recognized as a new viable therapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To assess their efficacy, we conducted a meta-analysis of existing preclinical experimental animal models of EVs for ALI treatment. Methods: The database was systematically interrogated for pertinent data encompassing the period from January 2010 to April 2022 concerning interventions involving extracellular vesicles (EVs) in animal models of acute lung injury (ALI). The lung injury score was selected as the primary outcome measure for statistical analysis. Meta-analyses were executed utilizing RevMan 5.3 and State15.1 software tools. Results: The meta-analyses comprised 31 studies, exclusively involving animal models of acute lung injury (ALI), categorized into two cohorts based on the presence or absence of extracellular vesicle (EV) intervention. The statistical outcomes from these two study groups revealed a significant reduction in lung injury scores with the administration of stem and progenitor cell-derived EVs (SMD = -3.63, 95% CI [-4.97, -2.30], P < 0.05). Conversely, non-stem cell-derived EVs were associated with an elevation in lung injury scores (SMD = -4.34, 95% CI [3.04, 5.63], P < 0.05). EVs originating from stem and progenitor cells demonstrated mitigating effects on alveolar neutrophil infiltration, white blood cell counts, total cell counts in bronchoalveolar lavage fluid (BALF), lung wet-to-dry weight ratios (W/D), and total protein in BALF. Furthermore, pro-inflammatory mediators exhibited down-regulation, while anti-inflammatory mediators demonstrated up-regulation. Conversely, non-stem cell-derived EVs exacerbated lung injury. Conclusion: In preclinical animal models of acute lung injury (ALI), the administration of extracellular vesicles (EVs) originating from stem and progenitor cells demonstrably enhances pulmonary function. This ameliorative effect is attributed to the mitigation of pulmonary vascular permeability and the modulation of immune homeostasis, collectively impeding the progression of inflammation. In stark contrast, the utilization of EVs derived from non-stem progenitor cells exacerbates the extent of lung injury. These findings substantiate the potential utility of EVs as a novel therapeutic avenue for addressing acute lung injury. [ABSTRACT FROM AUTHOR]

Heart surgery may be complicated by acute lung injury and adult respiratory distress syndrome. Expression and release of mucins MUC5AC and MUC5B in the lungs has been reported to be increased in acute lung injury. The aim of our study was to [1] investigate the perioperative changes of MUC5AC, MUC5B and other biomarkers in mini-bronchoalveolar lavage (minBAL), and [2] relate these to clinical outcomes after cardiac surgery. In this prospective cohort study in 49 adult cardiac surgery patients pre- and post-surgery non-fiberscopic miniBAL fluids were analysed for MUC5AC, MUC5B, IL-8, human neutrophil elastase, and neutrophils. All measured biomarkers increased after surgery. Perioperative MUC5AC-change showed a significant negative association with postoperative P/F ratio (p = 0.018), and a positive association with ICU stay (p = 0.027). In conclusion, development of lung injury after cardiac surgery and prolonged ICU stay are associated with an early increase of MUC5AC as detected in mini-BAL. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Metabolic syndrome is known to predict outcomes in COVID-19 acute respiratory distress syndrome (ARDS) but has never been studied in non- COVID-19 ARDS. We therefore aimed to determine the association of metabolic syndrome with mortality among ARDS trial subjects. DESIGN: Retrospective cohort study of ARDS trials' data. SETTING: An ancillary analysis was conducted using data from seven ARDS Network and Prevention and Early Treatment of Acute Lung Injury Network randomized trials within the Biologic Specimen and Data Repository Information Coordinating Center database. PATIENTS: Hospitalized patients with ARDS and metabolic syndrome (defined by obesity, diabetes, and hypertension) were compared with similar patients without metabolic syndrome (those with less than three criteria). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day mortality. Among 4288 ARDS trial participants, 454 (10.6%) with metabolic syndrome were compared with 3834 controls (89.4%). In adjusted analyses, the metabolic syndrome group was associated with lower 28-day and 90-day mortality when compared with control (adjusted odds ratio [aOR], 0.70 [95% CI, 0.55-0.89] and 0.75 [95% CI, 0.60-0.95], respectively). With each additional metabolic criterion from 0 to 3, adjusted 28-day mortality was reduced by 18%, 22%, and 40%, respectively. In subgroup analyses stratifying by ARDS etiology, mortality was lower for metabolic syndrome vs. control in ARDS caused by sepsis or pneumonia (at 28 d, aOR 0.64 [95% CI, 0.48--0.84] and 90 d, aOR 0.69 [95% CI, 0.53-0.89]), but not in ARDS from noninfectious causes (at 28 d, aOR 1.18 [95% CI, 0.70-1.99] and 90 d, aOR 1.26 [95% CI, 0.77-2.06]). Interaction p = 0.04 and p = 0.02 for 28- and 90-day comparisons, respectively. CONCLUSIONS: Metabolic syndrome in ARDS was associated with a lower risk of mortality in non-COVID-19 ARDS. The relationship between metabolic in- flammation and ARDS may provide a novel biological pathway to be explored in precision medicine-based trials. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is characterized by an exacerbated inflammatory response, severe damage to the alveolar-capillary barrier and a secondary infiltration of protein-rich fluid into the airspaces, ultimately leading to respiratory failure. Resolution of ARDS depends on the ability of the alveolar epithelium to reabsorb lung fluid through active transepithelial ion transport, to control the inflammatory response, and to restore a cohesive and functional epithelium through effective repair processes. Interestingly, several lines of evidence have demonstrated the important role of potassium (K+) channels in the regulation of epithelial repair processes. Furthermore, these channels have previously been shown to be involved in sodium/fluid absorption across alveolar epithelial cells, and we have recently demonstrated the contribution of KvLQT1 channels to the resolution of thiourea-induced pulmonary edema in vivo. The aim of our study was to investigate the role of the KCNQ1 pore-forming subunit of KvLQT1 channels in the outcome of ARDS parameters in a model of acute lung injury (ALI). We used a molecular approach with KvLQT1-KO mice challenged with bleomycin, a well-established ALI model that mimics the key features of the exudative phase of ARDS on day 7. Our data showed that KvLQT1 deletion exacerbated the negative outcome of bleomycin on lung function (resistance, elastance and compliance). An alteration in the profile of infiltrating immune cells was also observed in KvLQT1-KO mice while histological analysis showed less interstitial and/or alveolar inflammatory response induced by bleomycin in KvLQT1-KO mice. Finally, a reduced repair rate of KvLQT1-KO alveolar cells after injury was observed. This work highlights the complex contribution of KvLQT1 in the development and resolution of ARDS parameters in a model of ALI. [ABSTRACT FROM AUTHOR]

Cytokine storm and ROS overproduction in the lung always lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a very short time. Effectively controlling cytokine storm release syndrome (CRS) and scavenging ROS are key to the prevention and treatment of ALI/ARDS. In this work, the naringin nanoparticles (Nar-NPs) were prepared by the emulsification and evaporation method; then, the mesenchymal stem cell membranes (CMs) were extracted and coated onto the surface of the Nar-NPs through the hand extrusion method to obtain the biomimetic CM@Nar-NPs. In vitro, the CM@Nar-NPs showed good dispersity, excellent biocompatibility, and biosafety. At the cellular level, the CM@Nar-NPs had excellent abilities to target inflamed macrophages and the capacity to scavenge ROS. In vivo imaging demonstrated that the CM@Nar-NPs could target and accumulate in the inflammatory lungs. In an ALI mouse model, intratracheal (i.t.) instillation of the CM@Nar-NPs significantly decreased the ROS level, inhibited the proinflammatory cytokines, and remarkably promoted the survival rate. Additionally, the CM@Nar-NPs increased the expression of M2 marker (CD206), and decreased the expression of M1 marker (F4/80) in septic mice, suggesting that the Nar-modulated macrophages polarized towards the M2 subtype. Collectively, this work proves that a mesenchymal stem cell membrane-based biomimetic nanoparticle delivery system could efficiently target lung inflammation via i.t. administration; the released payload inhibited the production of inflammatory cytokines and ROS, and the Nar-modulated macrophages polarized towards the M2 phenotype which might contribute to their anti-inflammation effects. This nano-system provides an excellent pneumonia-treated platform with satisfactory biosafety and has great potential to effectively deliver herbal medicine. [ABSTRACT FROM AUTHOR]

Inflammation is an important pathological process of many acute and chronic diseases, such as sepsis, arthritis, and cancer. Many factors can lead to an inflammatory state of the body, among which bacterial infection plays an important role. Bacterial infection often leads to sepsis, acute lung injury (ALI), or its more serious form of acute respiratory distress syndrome, which are the main fatal diseases in intensive care units. Costunolide has been reported to possess excellent anti-inflammatory activity; however, whether it can affect inflammation induced by gram-negative bacterial is still unclear. Lipopolysaccharide (LPS) stimulated mouse peritoneal macrophages (MPMs) to release proinflammatory cytokines was used as the cell model. The mouse model of sepsis and ALI was built through injecting intravenously and intratracheally of LPS. In the present study, costunolide inhibited LPS-induced inflammatory response through IKK/NF-κB signaling pathway in macrophages. In vivo, costunolide attenuated LPS-induced septic death in mice. Meanwhile, costunolide treatment alleviated LPS-induced lung injury and inflammation via inhibiting the infiltration of inflammatory cells and the expression of inflammatory cytokines. Taken together, these results demonstrated that costunolide could attenuate gram-negative bacterial induced inflammation and diseases and might be a potential candidate for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary complications contribute significantly to nonrelapse mortality following hematopoietic stem cell transplantation (HCT). Identifying patients at high risk can help enroll such patients into clinical studies to better understand, prevent, and treat posttransplantation respiratory failure syndromes. Objectives: To develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. Methods: Patients underwent HCT between January 1, 2019, and December 31, 2021, at one of three institutions. Those treated in Rochester, MN, formed the derivation cohort, and those treated in Scottsdale, AZ, or Jacksonville, FL, formed the validation cohort. The primary outcome was the development of acute respiratory distress syndrome (ARDS), with secondary outcomes including the need for invasive mechanical ventilation (IMV) and/or noninvasive ventilation (NIV). Predictors were based on prior case-control studies. Measurements and Main Results: Of 2,450 patients undergoing stem cell transplantation, there were 1,718 hospitalizations (888 patients) in the training cohort and 1,005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from prehospital predictors and 11 points from posttransplantation or early (<24-h) in-hospital predictors. The model performed well in predicting ARDS (C-statistic, 0.905; 95% confidence interval [CI], 0.870–0.941) and the need for IMV and/or NIV (C-statistic, 0.863; 95% CI, 0.828–0.898). The test cohort differed markedly in demographic, medical, and hematologic characteristics. The model also performed well in this setting in predicting ARDS (C-statistic, 0.841; 95% CI, 0.782–0.900) and the need for IMV and/or NIV (C-statistic, 0.872; 95% CI, 0.831–0.914). Conclusions: A novel prediction model incorporating data elements from the pretransplantation, posttransplantation, and early in-hospital domains can reliably predict the development of post-HCT acute respiratory failure. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present life-threatening conditions characterized by inflammation and endothelial injury, leading to increased vascular permeability and lung edema. Key players in the pathogenesis and resolution of ALI are macrophages (Mφs) and endothelial cells (ECs). The crosstalk between these two cell types has emerged as a significant focus for potential therapeutic interventions in ALI. This review provides a brief overview of the roles of Mφs and ECs and their interplay in ALI/ARDS. Moreover, it highlights the significance of investigating perivascular macrophages (PVMs) and immunomodulatory endothelial cells (IMECs) as crucial participants in the Mφ–EC crosstalk. This sheds light on the pathogenesis of ALI and paves the way for innovative treatment approaches. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. Recently, increasing evidence supports activated inflammation and gasdermin D (GSDMD)-mediated pyroptosis in macrophage are closely associated with ALI. Basic helix-loop-helix family member e40 (Bhlhe40) is a transcription factor that is comprehensively involved in inflammation. However, there is little experimental evidence connecting Bhlhe40 and GSDMD-driven pyroptosis. The study sought to verify the hypothesis that Bhlhe40 is required for GSDMD-mediated pyroptosis in lipopolysaccharide (LPS)-induced inflammatory injury. Method: We performed studies using Bhlhe40-knockout (Bhlhe40 −/−) mice, small interfering RNA (siRNA) targeting Bhlhe40 and pyroptosis inhibitor disulfiram to investigate the potential roles of Bhlhe40 on LPS-induced ALI and the underlying mechanisms. Results: Bhlhe40 was highly expressed in total lung tissues and macrophages of LPS-induced mice. Bhlhe40−/− mice showed alleviative lung pathological injury and inflammatory response upon LPS stimulation. Meanwhile, we found that Bhlhe40 deficiency significantly suppressed GSDMD-mediated pyroptosis in macrophage in vivo and in vitro. By further mechanistic analysis, we demonstrated that Bhlhe40 deficiency inhibited GSDMD-mediated pyroptosis and subsequent ALI by repressing canonical (caspase-1-mediated) and non-canonical (caspase-11-mediated) signaling pathways in vivo and in vitro. Conclusion: These results indicate Bhlhe40 is required for LPS-induced ALI. Bhlhe40 deficiency can inhibit GSDMD-mediated pyroptosis and therefore alleviate ALI. Targeting Bhlhe40 may be a potential therapeutic strategy for LPS-induced ALI. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is one of the most common complications in COVID‐19 and also a syndrome of acute respiratory failure with high mortality rates, but lacks effective therapeutic drugs. Natural products provide inspiration and have proven to be the most valuable source for bioactive molecule discovery. In this study, the chemical evolution of the natural product Tanshinone IIA (Tan‐IIA) to achieve a piperidine‐fused scaffold through a synthetic route of pre‐activation, multi‐component reaction, and post‐modification is presented. Through biological evaluation, it is pinpointed that compound 8b is a standout candidate with remarkable anti‐inflammation and anti‐oxidative stress properties, coupled with low toxicity. The mechanistic study unveils a multifaceted biological profile of 8b and shows that 8b is highly efficient in vivo for the treatment of ALI. Therefore, this work not only provides an effective strategy for the treatment of ALI, but also offers a distinctive natural product‐inspired drug discovery. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus to cause acute respiratory distress syndrome (ARDS) and contains four structural proteins: spike, envelope, membrane, and nucleocapsid. An increasing number of studies have demonstrated that all four structural proteins of SARS-CoV-2 are capable of causing lung injury, even without the presence of intact virus. Therefore, the topic of SARS-CoV-2 structural protein-evoked lung injury warrants more attention. In the current article, we first synopsize the structural features of SARS-CoV-2 structural proteins. Second, we discuss the mechanisms for structural protein-induced inflammatory responses in vitro. Finally, we list the findings that indicate structural proteins themselves are toxic and sufficient to induce lung injury in vivo. Recognizing mechanisms of lung injury triggered by SARS-CoV-2 structural proteins may facilitate the development of targeted modalities in treating COVID-19. [ABSTRACT FROM AUTHOR]

Background: Morbidity and mortality rates associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are high (30–40%). Nuclear factor-kappa B (NF-κB) is a transcription factor, associated with transcription of numerous cytokines leading to cytokine storm, and thereby, plays a major role in ALI/ARDS and in advanced COVID-19 syndrome. Methods: Considering the role of NF-κB in ALI, cost-effective in silico approaches were utilized in the study to identify potential NF-κB inhibitor based on the docking and pharmacokinetic results. The identified compound was then pharmacologically validated in lipopolysaccharide (LPS) rodent model of acute lung injury. LPS induces ALI by altering alveolar membrane permeability, recruiting activated neutrophils and macrophages to the lungs, and compromising the alveolar membrane integrity and ultimately impairs the gaseous exchange. Furthermore, LPS exposure is associated with exaggerated production of various proinflammatory cytokines in lungs. Results: Based on in silico studies Olopatadine Hydrochloride (Olo), an FDA–approved drug was found as a potential NF-κB inhibitor which has been reported for the first time, and considered further for the pharmacological validation. Intraperitoneal LPS administration resulted in ALI/ARDS by fulfilling 3 out of the 4 criteria described by ATS committee (2011) published workshop report. However, treatment with Olo attenuated LPS-induced elevation of proinflammatory markers (IL-6 and NF-κB), oxidative stress, neutrophil infiltration, edema, and damage in lungs. Histopathological studies also revealed that Olo treatment significantly ameliorated LPS-induced lung injury, thus conferring improvement in survival. Especially, the effects produced by Olo medium dose (1 mg/kg) were comparable to dexamethasone standard. Conclusion: In nutshell, inhibition of NF-κB pathway by Olo resulted in protection and reduced mortality in LPS- induced ALI and thus has potential to be used clinically to arrest disease progression in ALI/ARDS, since the drug is already in the market. However, the findings warrant further extensive studies, and also future studies can be planned to elucidate its role in COVID-19-associated ARDS or cytokine storm. [ABSTRACT FROM AUTHOR]

Nowadays, acute respiratory distress syndrome (ARDS) still has a high mortality rate, and the alleviation and treatment of ARDS remains a major research focus. There are various causes of ARDS, among which pneumonia and non-pulmonary sepsis are the most common. Trauma and blood transfusion can also cause ARDS. In ARDS, the aggregation and infiltration of neutrophils in the lungs have a great influence on the development of the disease. Neutrophils regulate inflammatory responses through various pathways, and the release of neutrophils through neutrophil extracellular traps (NETs) is considered to be one of the most important mechanisms. NETs are mainly composed of DNA, histones, and granuloproteins, all of which can mediate downstream signaling pathways that can activate inflammatory responses, generate immune clots, and cause damage to surrounding tissues. At the same time, the components of NETs can also promote the formation and release of NETs, thus forming a vicious cycle that continuously aggravates the progression of the disease. NETs are also associated with cytokine storms and immune balance. Since DNA is the main component of NETs, DNase I is considered a viable drug for removing NETs. Other therapeutic methods to inhibit the formation of NETs are also worthy of further exploration. This review discusses the formation and mechanism of NETs in ARDS. Understanding the association between NETs and ARDS may help to develop new perspectives on the treatment of ARDS. [ABSTRACT FROM AUTHOR]

The article discusses ventilator-induced lung injury (VILI), which refers to the lung damage caused by mechanical ventilation. The different types of VILI, including barotrauma, volutrauma, atelectrauma, biotrauma, and ergotrauma, are explained. The article also explores the pathogenesis of VILI in healthy and injured lungs, as well as the assessment and clinical approach to VILI. The authors argue for a broader definition of VILI to include all direct and indirect pathological changes caused by mechanical ventilation. [Extracted from the article]

Background: Sivelestat, a neutrophil elastase inhibitor, is specifically developed to mitigate the occurrence of acute lung injury (ALI) in individuals who are undergoing cardiovascular surgery. However, its impact on patients who are at a heightened risk of developing ALI after scheduled cardiac surgery has yet to be determined. In order to address this knowledge gap, we undertook a study to assess the efficacy of sivelestat in protecting the lungs of these patients. Methods: We conducted a prospective cohort study involving 718 patients who were at high risk of developing postoperative acute lung injury (ALI) and underwent scheduled cardiac surgery between April 25th, 2022, and September 7th, 2023. Among them, 52 patients received sivelestat (administered at a dosage of 0.2mg/kg/h for 3 days), while 666 patients served as controls, not receiving sivelestat. The control conditions were the same for all patients, including ventilation strategy, extubating time, and fluid management. Subsequently, a propensity-score matched cohort was established, consisting of 40 patients in both the sivelestat and control groups. The primary outcome measure encompassed a composite of adverse outcomes, including 30-day mortality, ALI, acute respiratory distress syndrome (ARDS), and others. Secondary outcomes assessed included pneumonia, ventricular arrhythmias, mechanical ventilation (MV) time, and more. Results: After conducting propensity matching in our study, we observed that there were no significant differences in 30-day mortality between the sivelestat and control groups (0% vs 2.5%, P=0.32). However, the use of sivelestat exhibited a significant reduction in the incidence of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) compared to the control group (0% vs 55%, P< 0.01), pneumonia (0 vs 37.5%, P< 0.01), MV time (median:8 hours, IQR:4– 14.8 hours vs median: 15.2 hours, IQR:14– 16.3 hours, P< 0.01). Compared to the control group, the sivelestat could significantly decrease white cell count (P< 0.01), neutrophile percentage (P< 0.01) and C-reactive protein (P< 0.01) in the period of postoperative 5 days. Conclusion: The prophylactic administration of sivelestat has shown promising results in reducing the occurrence of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with a heightened risk of developing these conditions after elective cardiac surgery. Our study findings indicate that sivelestat may provide protective effects by suppressing inflammation triggered by neutrophil activation, thereby safeguarding pulmonary function. Registration: ChiCTR2200059102, https://www.chictr.org.cn/showproj.html?proj=166643. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a complex disease with numerous causes. This review begins with a discussion of disease development from direct or indirect pulmonary insults, as well as varied pathogenesis. The heterogeneous nature of ALI is then elaborated upon, including its epidemiology, clinical manifestations, potential biomarkers, and genetic contributions. Although no medication is currently approved for this devastating illness, supportive care and pharmacological intervention for ALI treatment are summarized, followed by an assessment of the pathophysiological gap between human ALI and animal models. Lastly, current research progress on advanced nanomedicines for ALI therapeutics in preclinical and clinical settings is reviewed, demonstrating new opportunities towards developing an effective treatment for ALI. [ABSTRACT FROM AUTHOR]

Background: The complement system is an important arm of immune defense bringing innate and adaptive immunity. Although originally regarded as a major complementary defense mechanism against pathogens, continuously emerging evidence has uncovered a central role of this complex system in several diseases including lung pathologies. Main body: Complement factors such as anaphylatoxins C3a and C5a, their receptors C3aR, C5aR and C5aR2 as well as complement inhibitory proteins CD55, CD46 and CD59 have been implicated in pathologies such as the acute respiratory distress syndrome, pneumonia, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, and lung cancer. However, the exact mechanisms by which complement factors induce these diseases remain unclear. Several complement-targeting monoclonal antibodies are reported to treat lung diseases. Conclusions: The complement system contributes to the progression of the acute and chronic lung diseases. Better understanding of the underlying mechanisms will provide groundwork to develop new strategy to target complement factors for treatment of lung diseases. [ABSTRACT FROM AUTHOR]

Background: Various Positive End-Expiratory Pressure (PEEP) titration strategies have been proposed to optimize ventilation in patients with acute respiratory distress syndrome (ARDS). We aimed to compare PEEP titration strategies based on electrical impedance tomography (EIT) to methods derived from respiratory system mechanics with or without esophageal pressure measurements, in terms of PEEP levels and association with recruitability. Methods: Nineteen patients with ARDS were enrolled. Recruitability was assessed by the estimated Recruitment-to-Inflation ratio (R/Iest) between PEEP 15 and 5 cmH2O. Then, a decremental PEEP trial from PEEP 20 to 5 cmH2O was performed. PEEP levels determined by the following strategies were studied: (1) plateau pressure 28–30 cmH2O (Express), (2) minimal positive expiratory transpulmonary pressure (Positive PLe), (3) center of ventilation closest to 0.5 (CoV) and (4) intersection of the EIT-based overdistension and lung collapse curves (Crossing Point). In addition, the PEEP levels determined by the Crossing Point strategy were assessed using different PEEP ranges during the decremental PEEP trial. Results: Express and CoV strategies led to higher PEEP levels than the Positive PLe and Crossing Point ones (17 [14–17], 20 [17–20], 8 [5–11], 10 [8–11] respectively, p < 0.001). For each strategy, there was no significant association between the optimal PEEP level and R/Iest (Crossing Point: r2 = 0.073, p = 0.263; CoV: r2 < 0.001, p = 0.941; Express: r2 < 0.001, p = 0.920; Positive PLe: r2 = 0.037, p = 0.461). The PEEP level obtained with the Crossing Point strategy was impacted by the PEEP range used during the decremental PEEP trial. Conclusions: CoV and Express strategies led to higher PEEP levels than the Crossing Point and Positive PLe strategies. Optimal PEEP levels proposed by these four methods were not associated with recruitability. Recruitability should be specifically assessed in ARDS patients to optimize PEEP titration. [ABSTRACT FROM AUTHOR]

Hippophae rhamnoides exhibit a wide variety of medicinal and pharmacological effects. The present study aims to determine the role of ethanol extract of H. rhamnoides on oleic acid (OA)-induced acute respiratory distress syndrome (ARDS) in rats. Male rats were randomly divided into the following groups: (I) Control, (II) OA, and (III) OA+H. rhamnoides. H. rhamnoides extract (500 mg/kg) was given orally for 2 weeks before OA in Group III. Levels of total antioxidant capacity, total oxidant status (TOS), myeloperoxidase (MPO), mitogen-activated protein kinase (MAPK), acetylcholinesterase (AChE), and angiotensin-converting enzyme (ACE) were quantified by enzyme-linked immunosorbent assay (ELISA). Real time quantitative polymerase chain reaction was utilized to evaluate the expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and matrix metalloproteinase 2 (MMP2). Also, Caspase-3 immunostaining and expression were performed to evaluate apoptosis. Compared with the OA group, there was a significantly decrease in the levels of MPO, TOS, MAPK, and ACE and in the expression of NF-κB, TNF-α, IL-6, MMP2, and Caspase-3 in the H. rhamnoides administration group. Moreover, the activity of AChE and level of TAS were substantially higher in the H. rhamnoides administration compared with the OA group. The findings in the study suggest that the protective effect of H. rhamnoides pretreatment may act through inhibition of the ACE activity, releasing AChE, regulation of inflammatory cytokine levels, and suppression of apoptotic process in ARDS. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a devastating respiratory disorder, characterized by overwhelming inflammation in the alveoli without effective pharmacological treatment. We aimed to investigate the effect and mechanism of angiotensin II type 2 receptor (AT2R) agonist, Compound 21 (C21), on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. The protective effect of C21 was evaluated via enzyme-linked immunosorbent assay (ELISA), Western blot (WB), real-time PCR, and fluorescence microscopy in LPS-challenged THP1-derived macrophages. Besides, the in vivo efficacy of C21 was assessed using cell counting, ELISA, protein quantification, hematoxylin–eosin (H&E) staining, and WB in an LPS-induced ALI mouse model. The results showed that C21 significantly inhibited the secretion of pro-inflammatory cytokines (CCL-2, IL-6), overproduction of intracellular ROS, and activation of inflammatory pathways (NF-κB/NLRP3, p38/MAPK) in THP-1 cell-derived macrophages stimulated by LPS. In in vivo study, intraperitoneal injection of C21 could reduce airway leukocytes accumulation and chemokine/cytokine (keratinocyte chemoattractant (KC), IL-6) generation, as well as alleviate diffuse alveolar damage induced by LPS. Conclusively, the AT2R agonist C21 significantly inhibited LPS-stimulated excess inflammatory responses and oxidative stress in macrophages. Meanwhile, C21 could effectively alleviate acute inflammation and tissue damage in the lungs of ALI mice challenged by LPS. The results of this study bring new hope for the early treatment of ALI/ARDS. [ABSTRACT FROM AUTHOR]

Acute lung injury is a life-threatening condition characterized by hypoxemia, pulmonary edema, and inflammation. This comprehensive review delves into the intricate landscape of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), shedding light on the multifaceted challenges and advancements in their understanding and treatment. The exploration of pathological features, pharmacological interventions, and long-term outcomes unveils the complexities inherent in managing these critical respiratory conditions. The etiology of ALI/ARDS is diverse and includes direct and indirect insults to the lungs. Key findings underscore the hurdles posed by the heterogeneous patient population, emphasizing the imperative of tailoring interventions based on individual characteristics. Ambiguities surrounding optimal timing, dosing, and duration of pharmacological interventions highlight the need for standardized protocols to ensure consistency in treatment approaches. While advancements in mechanical ventilation, fluid management, and pharmacological agents show promise, the absence of reliable biomarkers for treatment response prediction remains a significant limitation. Recommendations for clinical practice encompass personalized and targeted approaches, leveraging technological advancements for individualized care, and advocating for standardized protocols. The pharmacology of ALI/ARDS is complex and challenging, as no specific drug has been proven to be effective in treating ALI. However, several pharmacological agents have been tested or are under investigation for modulating the inflammatory response, reducing oxidative stress, enhancing alveolar fluid clearance, and preventing fibrosis. On a policy level, there is a call for increased research initiatives, specifically in biomarker identification and large-scale trials for emerging treatments. Acknowledging limitations in the evolving nature of research and study heterogeneity, this review stands as a timely and informative resource, providing valuable insights for healthcare practitioners and policymakers navigating the intricate landscape of ALI and ARDS. Implementing the outlined recommendations holds the potential to enhance patient care and guide future research endeavors in this critical field. [ABSTRACT FROM AUTHOR]