Mesenchymal stem cells (MSCs) are a potential therapy for acute respiratory distress syndrome (ARDS), but their mechanisms in repairing mitochondrial damage in ARDS endothelial cells remain unclear.

We first examined MSCs' mitochondrial transfer ability and mechanisms to mouse pulmonary microvascular endothelial cells (MPMECs) in ARDS. Then, we investigated how MSC-mediated mitochondrial transfer affects the repair of endothelial damage. Finally, we elucidated the mechanisms by which MSC-mediated mitochondrial transfer promotes vascular regeneration.

Compared to mitochondrial-damaged MSCs, normal MSCs showed a significantly higher mitochondrial transfer rate to MPMECs, with increases of 41.68% in vitro (P < 0.0001) and 10.50% in vivo (P = 0.0005). Furthermore, MSC-mediated mitochondrial transfer significantly reduced reactive oxygen species (P < 0.05) and promoted proliferation (P < 0.0001) in MPMECs. Finally, MSC-mediated mitochondrial transfer significantly increased the activity of the tricarboxylic acid (TCA) cycle (MD of CS mRNA: 23.76, P = 0.032), and further enhanced fatty acid synthesis (MD of FAS mRNA: 6.67, P = 0.0001), leading to a 6.7-fold increase in vascular endothelial growth factor release from MPMECs and promoted vascular regeneration in ARDS.

MSC-mediated mitochondrial transfer to MPMECs activates the TCA cycle and fatty acid synthesis, promoting endothelial proliferation and pro-angiogenic factor release, thereby enhancing vascular regeneration in ARDS.

Exosomes derived from specific cells may be useful for targeted drug delivery, but tracking them in vivo is essential for their clinical application. However, their small size and complex structure challenge the development of exosome-tracking techniques, and traditional labeling methods are limited by weak affinity and potential toxicity. To address these issues, here we developed a novel bio-orthogonal labeling strategy based on phosphatidylinositol derivatives to fluorescently label exosomes from various human and mouse cell types. The different cell-derived exosomes revealed organ-specific distribution patterns and a favorable safety profile. Notably, 4T1 cell-derived exosomes specifically targeted the lungs. When used as drug carriers loaded with anti-inflammatory resveratrol, these exosomes showed significant therapeutic efficacy in mice with acute respiratory distress syndrome (ARDS), effectively reducing inflammatory responses, mitigating pulmonary fibrosis, and restoring lung tissue morphology and function. Our findings provide a novel exosome labeling strategy and an invaluable tool for their in vivo tracking and targeting screening, while exosomes that specifically target the lungs offer a potential therapeutic strategy for organ-specific diseases such as ARDS.

Macrophage polarization plays a crucial role in acute respiratory distress syndrome (ARDS). Recently, mounting evidence has uncovered that endothelial progenitor cells (EPCs) secreted exosomes (EPCs-Exos) exert obvious therapeutic effects on the pathological inflammatory process of ARDS, but its potential mechanism is rarely reported.

The primary mouse EPCs and EPCs-Exos were isolated and identified. Absorption of EPCs-Exos by RAW264.7 cells was examined by PKH-26 staining. The polarization of RAW264.7 cells was evaluated by flow cytometry and RT-qPCR analysis. Molecular interactions were verified by dual luciferase assay, RNA pull-down and RNA immunocoprecipitation assays. ARDS mouse model was established, and pathological changes and expressions of related molecules were detected by HE staining, RT-qPCR and western blotting.

EPCs-Exos could be transferred to macrophages, and effectively reversed LPS-induced polarization of macrophages from M2 to M1 phenotype; however, these changes were diminished by activation of TLR4/NF-κB pathway. MiR-103-3p was proved to be enriched in EPC-Exos and could transfer to macrophage and inactivating TLR4/NF-κB pathway via directly binding to TLR4 3'-UTR. Moreover, miR-103-3p overexpression elevated macrophage M2 polarization and repressed M1 polarization in LPS-treated cells by inhibiting TLR4/NF-κB pathway, and knockdown of miR-103-3p in EPC-Exos abolished the regulatory roles of EPC-Exos on macrophage polarization in vitro, and lung inflammatory injury in vivo. HnRNPA2B1 was proved to interact with miR-103-3p and responsible for its exosomal secretion, which repressed pro-inflammatory macrophage polarization.

These findings suggested that hnRNPA2B1-mediated exosomal delivery of miR-103-3p from EPCs protected against macrophage inflammation in ARDS by inactivation of TLR4/NF-κB pathway.

To investigate whether bone marrow mesenchymal stem cells derived exosomes (BMSCs-exo) can alleviate sepsis-induced lung injury and its related mechanism by inhibiting ferroptosis of macrophages.

RAW264.7 cells were first stimulated with lipopolysaccharide (LPS) to observe whether macrophage ferroptosis occurred. After pre-treating BMSCs with the exosome inhibitor GW4869, the lung-protective effect was observed to determine if it was eliminated. Furthermore, BMSCs-exo was extracted to clarify if it could exert effects like BMSCs. Finally, key molecules responsible for the effects were identified through sequencing and other related techniques.

Following stimulation with LPS, the expression of GPX4 in RAW264.7 cells decreased significantly, while the expression of PTGS2 increased significantly. The intracellular GSH content decreased, while MDA content increased. BMSCs-exo reversed the decrease in GPX4 and increase in PTGS2, increased GSH and decreased MDA. Sequencing revealed that lncRNA SNHG12 in macrophages was significantly upregulated after co-culture with BMSCs-exo. Knockdown of lncRNA SNHG12 in BMSCs via siRNA resulted in a significant decrease in the inhibitory effect on macrophage ferroptosis both in vivo and in vitro.

BMSCs-exo can inhibit macrophage ferroptosis through lncRNA SNHG12, thereby alleviating the sepsis-induced lung injury and improving the survival rate.

Critically ill patients with acute respiratory distress syndrome (ARDS) are one of the leading causes of death worldwide. Although a number of relevant predictors of ARDS have been identified, the current predictors are not satisfactory. Recent studies have revealed the predictive value of red blood cell distribution width (RDW) for ARDS. Therefore, we conducted the first meta-analysis to explore the predictive value of RDW in critically ill patients with ARDS.

A literature search was conducted to identify relevant observational studies from January 1, 2000, to August 1, 2024. Eligible studies were screened and data were extracted. The standardized mean difference (SMD) with 95% confidence interval (CI) of the RDW levels for each study were combined under the random-effect model.

Ten articles with a total of 2252 participants were included in the study. Elevated RDW levels on admission was significantly associated with significantly associated with an increased risk of ARDS morbidity (SMD = 1.09; 95% CI = 0.35-1.82; P = .004), and also significantly associated with an increased risk of ARDS mortality (SMD = 0.73; 95% CI = 0.53-0.93; P < .00001). Subgroup analysis further showed RDW ≥ 14.0 on admission could be regarded as a predictive morbidity factor for ARDS (SMD = 1.36; 95% CI = 0.66-2.07; P = .0002), and RDW ≥ 15.5 on admission could be also regarded as a predictive mortality factor for ARDS (SMD = 0.73; 95% CI = 0.49-0.97; P < .00001).

RDW levels seems to be a useful tool for predicting the morbidity and mortality of critically ill patients with ARDS.

The cardiopulmonary vasculature and its associated endothelial cells (ECs) play an essential role in sustaining life by ensuring the delivery of oxygen and nutrients. Beyond these foundational functions, ECs serve as key regulators of immune responses. Recent advances in single-cell RNA sequencing have revealed that the cardiopulmonary vasculature is composed of diverse EC subpopulations, some of which exhibit specialized immunomodulatory properties. Evidence for immunomodulation includes distinct expression profiles associated with antigen presentation, cytokine secretion, immune cell recruitment, translocation, and clearance - functions critical for maintaining homeostasis in the heart and lungs. In cardiopulmonary diseases, ECs undergo substantial transcriptional reprogramming, leading to a shift from homeostasis to an activated state marked by heightened immunomodulatory activity. This transformation has highlighted the critical role for ECs in disease pathogenesis and their potential as future therapy targets. This Review emphasizes the diverse functions of ECs in the heart and lungs, particularly adaptive and maladaptive immunoregulatory roles in cardiopulmonary health and disease.

Antibiotic resistance has amplified the threat of bacterial-induced acute lung injury (ALI) to human health. In the quest for novel therapeutic strategies, natural products have shown promise in mitigating the severity of this condition. In this study, we explored the protective effects of pelargonidin-3-O-galactoside (Pg3gal) on Klebsiella pneumoniae (KP)-induced ALI and its underlying mechanisms. Our findings indicated that Pg3gal mitigated lung histopathological changes and edema by inhibiting the migration and infiltration of immune cells and by reducing the secretion of pro-inflammatory cytokines. Molecular docking and surface plasmon resonance analyses revealed that Pg3gal bound to CD38 with high affinity. Further investigation showed that Pg3gal downregulated CD38 expression by promoting its ubiquitination. The reduction of CD38 elevated NAD+ levels and SIRT1 expression and inhibited NF-κB p65 acetylation, thereby suppressing NLRP3 inflammasome-mediated pyroptosis. Our research demonstrates that Pg3gal exerts protective effects against KP-induced ALI by inhibiting pyroptosis through the CD38/SIRT1/NF-κB/NLRP3 signaling pathway, highlighting its potential as a therapeutic agent for ALI.

Human males and females show differences in the incidence of neutrophil-associated diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, and differences in neutrophil physiological responses such as responses to infection, tissue damage, and chemotactic factors. However, little is known about the basis of sex-based differences in human neutrophils.

Starting with human neutrophils from healthy donors, we used RNA-seq to examine total RNA profiles, RNAs not associated with ribosomes and thus not being translated, RNAs in monosomes, and RNAs in polysomes and thus heavily translated.

There were sex-based differences in the levels of RNAs across free RNA, monosome, and polysome fractions. Male neutrophils had increased levels of mRNAs encoding mitochondrial proteins in the free RNA fractions, indicating low levels of translation. The polysomes of male neutrophils were enriched for mRNAs encoding cytoskeletal organization, cell motility, and cell activation. The polysomes of female neutrophils were enriched for mRNAs associated the regulation of metabolic processes, cytokine responses, and mitochondrial proteins.

These data indicate that male and female neutrophils have different expression patterns and different translation efficiency of some mRNAs. This may contribute to the observed sex-based differences in neutrophil behavior and neutrophil-associated disease incidence and severity.

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), represent critical respiratory failures with high mortality rates and limited treatment options. While the flavonoid rutin exhibits documented anti-inflammatory and antioxidant properties, its therapeutic mechanisms in ALI/ARDS remain unclear. This study investigated rutin's efficacy against lipopolysaccharide (LPS)-induced ALI in mice, with a mechanistic focus on the cGAS-STING pathway and NLRP3 inflammasome activation.

Male C57BL/6 mice were divided into Vehicle control, LPS induction, LPS + rutin co-treatment, and Rutin monotherapy groups. ALI was induced by intratracheal LPS challenge, and rutin was administered via gavage. Proteomics analysis, histological evaluation, immunohistochemistry, TUNEL staining, immunofluorescence, RT-qPCR, western blot, ELISA, and oxidative stress assays were performed to assess the effects of rutin on ARDS.

The proteomic profiling of lung tissues from LPS-challenged mice identified significant dysregulation of proteins integral to the cGAS-STING cascade and pyroptotic processes. Gene ontology and KEGG pathway analyses underscored the pivotal role of immune and inflammatory responses in ALI, particularly in cytosolic DNA-sensing and NOD-like receptor signaling pathways. Rutin administration significantly alleviated LPS-induced lung injury, reducing oxidative stress, apoptosis, and proinflammatory cytokine levels (IL-6, IL-1β, TNF-α). Mechanistically, rutin demonstrated dual suppression: 1) inhibiting cGAS-STING activation through decreased expression of cGAS, STING, and phosphorylation of TBK1/IRF3 (P<0.05), and 2) attenuating NLRP3-mediated pyroptosis via downregulation of NLRP3-ASC-caspase1-GSDMD signaling (P<0.05). Pharmacological STING inhibition (C-176) validated the cGAS-STING-NLRP3 regulatory hierarchy in ALI pathogenesis.

These findings elucidate rutin's novel therapeutic mechanism through coordinated suppression of the cGAS-STING-NLRP3 axis, positioning it as a promising candidate for ALI/ARDS intervention.

Mediating protein citrullination, peptidyl arginine deiminase 2 (PAD2) has recently been reported to influence macrophage phenotypes. However, the mechanisms of PAD2 on macrophage function in Pseudomonas aeruginosa (PA)-induced acute lung injury syndrome (ALI) remains unclear. Utilizing single-cell RNA sequencing and mass spectrometry-based proteomics, a new citrullination site at arginine 171 (R171) is discovered within nuclear factor- κB (NF-κB) p65 catalyzed by PAD2, which modulates PAD2-NF-κB p65-importin α3 pathway and its downstream M1/M2 macrophage polarization. Building on these findings, a cell-specific targeted therapeutic strategy using gold nanoparticles (AuNPs) conjugated with a novel PAD2 inhibitor, AFM41a, and an intercellular adhesion molecule-1 (ICAM-1) antibody is developed. This approach enables the selective delivery of the inhibitor to M1-polarized macrophages in the PA-infected alveolar niche. In vivo, this nanomedicine reduces excessive inflammation and promotes M1-to-M2 polarization to inhibit ALI. This study highlights the role of PAD2-mediated citrullination in macrophage polarization and introduces a promising nanoparticle-based therapy for PA-induced ALI.

Studies have shown that sialylation of C1 esterase inhibitors is crucial for their interaction with histones, and histone-C1 esterase inhibitor complexes are detected in acute respiratory distress syndrome (ARDS), suggesting a potential role of sialylation in ARDS. However, the specific function of sialylation in ARDS remains unclear. Therefore, this study aimed to investigate the mechanism of sialylation-related genes (SRGs) in sepsis-induced ARDS.

The ARDS related datasets (GSE32707, GSE66890, and GSE151263) were included in this study. Candidate genes were identified by implementing differential expression analysis and weighted gene co-expression network analysis (WGCNA). Subsequently, further selection by machine learning and expression assessment confirmed the key genes related to sialylation in sepsis-induced ARDS. Following this, the predictive ability of key genes as a whole for sepsis-induced ARDS was evaluated by creating a nomogram model. Afterwards, enrichment analysis, construction of regulatory networks, and drug prediction analysis were implemented to further understand the molecular mechanisms of action of key genes. Furthermore, single-cell RNA sequencing (scRNA-seq) data analysis was conducted to obtain key cells. Additionally, cell communication and pseudo-time analyses were implemented. In the end, the expression levels of the key genes were assessed by collecting clinical samples.

CD19 and GPR65 were identified as key genes associated with sialylation in sepsis-induced ARDS. The constructed nomogram model demonstrated that CD19 and GPR65 as a whole exhibited robust predictive capability for sepsis-induced ARDS. Meanwhile, CD19 and GPR65 were also found to be significantly co-enriched in the apoptosis and B-cell receptor signaling pathway. In addition, some important regulators and drugs with targeting effects on key genes were predicted, such as NEAT1, OIP5-AS1, alprostadil, and tacrolimus. Further, the scRNA-seq data analysis identified nine cell types, among which CD14 monocytes (CD14Mono) was designated as the key cell. Importantly, GPR65 expression exhibited dynamic changes during differentiation of CD14Mono. Also, we found that CD19 was significantly up-regulated in ARDS group.

We identified CD19 and GPR65 as key genes associated with sialylation in sepsis-induced ARDS, highlighting CD14Mono as key cell type implicated in sepsis-induced ARDS. These findings offered theoretical support for understanding the mechanism of sialylation on sepsis-induced ARDS.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by a high mortality rate, and its treatment is relatively straightforward. The application of human umbilical cord mesenchymal stem cells (hucMSCs) for the treatment of ARDS has emerged as a novel therapeutic approach and has been the subject of extensive research. In this study, a mouse model of acute lung injury (ALI) was established, and hucMSCs were administered via tail vein injection to investigate the pathogenesis of ARDS and the protein alterations following hucMSC treatment. Data-independent acquisition (DIA) was employed for the proteomic analysis of lung tissue, which included the identification of differentially expressed proteins (DEPs) and their associated pathways. The relevant DEPs identified in the lung tissues of the three groups of mice included Arid5a, Mrpl4, Cxcl12, and Rnf121 (P <0.05). Silencing the expression of Cxcl12 in hucMSCs could significantly inhibit the therapeutic effect of hucMSCs in reducing the permeability of lung tissue and endothelial cells (P < 0.05). Additionally, the signaling pathways associated with the relevant DEPs were analyzed. The DEPs and the enriched pathways discussed herein provide valuable insights into the pathogenesis of ARDS and the potential applications of hucMSCs.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe hypoxemia and high mortality. Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, has emerged as a critical mechanism in ARDS pathogenesis. However, the molecular regulators of ferroptosis in ARDS remain unclear. This study integrates multi-omics analysis and experimental validation to identify ferroptosis-related targets in ARDS. Bronchoalveolar lavage fluid (BALF) samples from ARDS patients and healthy controls were subjected to proteomics and metabolomics analysis. Transcriptomic data from the GSE243066 dataset and ferroptosis-related gene databases were integrated to identify key genes. Functional enrichment analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. An LPS-induced ARDS mouse model was established for experimental validation, including Western blotting, histopathology, and ferroptosis-related biochemical assays. Multi-omics analysis identified YWHAE as a ferroptosis-associated gene significantly upregulated in ARDS. Functional enrichment revealed key pathways, including ferroptosis, hypoxia-inducible factor-1 signaling, and oxidative stress responses. Proteomic and transcriptomic integration highlighted 51 overlapping differentially expressed genes, with YWHAE emerging as a central hub in the protein-protein interaction network. Metabolomics analysis further revealed glutathione and cysteine metabolism as critical pathways linked to ferroptosis. In the ARDS mouse model, ferroptosis inhibitor ferrostatin-1 (Fer-1) attenuated LPS-induced lung injury, reduced oxidative stress markers, and downregulated YWHAE expression. This study identifies YWHAE as a novel ferroptosis-related target in ARDS through multi-omics analysis and experimental validation. These findings provide new insights into the molecular mechanisms of ferroptosis in ARDS and highlight YWHAE as a potential therapeutic target for future interventions.

Acute respiratory distress syndrome (ARDS) is a severe complication associated with a high mortality rate in patients with sepsis. Early identification of patients with sepsis at high risk of developing ARDS is crucial for timely intervention, optimization of treatment strategies, and improvement of clinical outcomes. However, traditional risk prediction methods are often insufficient. This study aimed to develop a machine learning (ML) model to predict the risk of ARDS in patients with sepsis using circulating immune cell parameters and other physiological data.

Clinical data from 10,559 patients with sepsis were obtained from the MIMIC-IV database. Principal component analysis (PCA) was used for dimensionality reduction and to comprehensively evaluate the models' predictive capabilities, we used several ML algorithms, including decision trees, k-nearest neighbors (KNN), logistic regression, naive Bayes, random forests, neural networks, XGBoost, and support vector machines (SVM) to predict ARDS risk. The model performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and F1 score. Shapley additive explanations (SHAP) were used to interpret the contribution of individual features to model predictions.

Among all models, XGBoost showed the best performance with an AUC of 0.764. Feature importance analysis revealed that mean arterial pressure, monocyte count, neutrophil count, pH, and platelet count were key predictors of ARDS risk in patients with sepsis. The SHAP analysis provided further information on how these features contributed to the model's predictions, aiding in interpretability and potential clinical applications.

The XGBoost model using circulating immune cell parameters accurately predicted the risk of ARDS in patients with sepsis. This model could be a useful tool for the early identification of high-risk patients and timely intervention; however, further validation and integration into clinical practice are required.

A 66-year-old man who was receiving treatment for B-cell non-Hodgkin lymphoma presented with fever. He tested positive for severe acute respiratory syndrome coronavirus 2 antigen. Chest computed tomography (CT) revealed pneumonia. Therefore, remdesivir was administered to the patient. However, steroid pulse therapy was initiated owing to the lack of any symptom improvement and a worsening of the CT findings. The patient developed recurrent fever following a reduction in the steroid dose. His respiratory condition gradually worsened, and he eventually died. Autopsy revealed diffuse alveolar damage. In high-risk patients with hematologic malignancy, COVID-19 vaccination should be repeated at shorter intervals to avoid increasing the viral load during the COVID-19 infection.

To investigate the effects and mechanisms of MFGE8 on LPS-induced endothelial-to-mesenchymal transition (EndoMT) and pulmonary fibrosis in human lung microvascular endothelial cells (HLMECs) and a mouse model of acute lung injury.

Serum MFGE8 levels were compared between ARDS patients and controls. In vitro, HLMECs were treated with LPS, siRNA targeting MFGE8, and recombinant human MFGE8 (rhMFGE8).HLMEC morphology, invasion, migration, and EndoMT markers (CD31, ɑ-SMA) were evaluated. BMP/Smad1/5-Smad4 signaling and Snail expression were assessed via immunofluorescence, western blotting, and qRT-PCR. In vivo, rhMFGE8 effects on pulmonary fibrosis and EndoMT were analyzed in a mouse model of acute lung injury.

MFGE8 levels were significantly reduced in ARDS patients, with higher levels correlating to better survival. In vitro, rhMFGE8 improved HLMEC morphology, reduced invasion and migration, and attenuated LPS-induced EndoMT by increasing CD31 and decreasing α-SMA. MFGE8 knockdown increased BMP/Smad1/5-Smad4 signaling and Snail expression, while rhMFGE8 inhibited these effects. In vivo, rhMFGE8 ameliorated pulmonary fibrosis and EndoMT in mice.

MFGE8 regulates LPS-induced EndoMT in HLMECs via the BMP/Smad1/5-Smad4 pathway and protects against pulmonary fibrosis in acute lung injury, suggesting it as a therapeutic target for ALI and ARDS.

Acute respiratory distress syndrome (ARDS) is characterized by severe respiratory failure and significant inflammation, leading to vascular and epithelial cell damage. The absence of effective pharmacologic treatments underscores the need for novel therapeutic approaches. Telocytes (TCs), a newly identified type of interstitial cells, have shown potential in tissue repair and angiogenesis, particularly through the release of exosomal microRNAs (miRNAs). Exosomes were isolated from LPS (lipopolysaccharide)-stimulated TCs and characterized using western blotting and nanoparticle tracking analysis. The role of exosomal miR-221 in angiogenesis was assessed through tube formation, migration, and proliferation assays in mouse vascular endothelial cells (MVECs). The JAK/STAT pathway's involvement in miR-221 regulation was determined using western blotting and qRT-PCR. A dual-luciferase assay confirmed E2F2 as a direct target of miR-221. ARDS mouse model was established via LPS instillation, and the therapeutic effects of TCs-derived exosomes were evaluated by histopathological scoring, cytokine analysis, and endothelial barrier integrity assays. Our findings demonstrated that exosomes from LPS-stimulated TCs significantly promoted angiogenesis, proliferation, and migration in MVECs. These effects were mediated by miR-221, which downregulated E2F2 expression, an important regulator of endothelial cell functions. The JAK/STAT pathway played a crucial role in miR-221 production, with pathway inhibition reducing miR-221 levels and attenuating its pro-angiogenic effects. In vivo, TCs-derived exosomes reduced lung inflammation and tissue damage in ARDS mice, effects that were reversed by miR-221 inhibition. These results suggested that TCs-derived exosomes promoted angiogenesis and alleviated ARDS through the JAK/STAT-miR-221-E2F2 axis.

Acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS), represents a critical condition characterized by extensive inflammation within the airways. Necroptosis, a form of cell death, has been implicated in the pathogenesis of various inflammatory diseases. However, the precise characteristics and mechanisms of necroptosis in ARDS remain unclear. Thus, our study seeks to elucidate the specific alterations and regulatory factors associated with necroptosis in ARDS and to identify potential therapeutic targets for the disease. We discovered that necroptosis mediates the progression of ALI through the activation and formation of the RIPK1/RIPK3/MLKL complex. Moreover, we substantiated the involvement of both MYD88 and TRIF in the activation of the TLR4 signaling pathway in ALI. Furthermore, we have developed a lipid micelle-encapsulated drug targeting MLKL in alveolar type II epithelial cells and successfully applied it to treat ALI in mice. This targeted nanoparticle selectively inhibited necroptosis, thereby mitigating epithelial cell damage and reducing inflammatory injury. Our study delves into the specific mechanisms of necroptosis in ALI and proposes novel targeted therapeutic agents, presenting innovative strategies for the management of ARDS.

Acute lung injury (ALI) has emerged as a critical illness, with sepsis-related ALI accounting for >80 %. In the context of bacterial infection, damage to the pulmonary microvascular barrier leads to inflammatory cell infiltration and plasma component extravasation into pulmonary interstitium. This disruption impairs gas exchange, resulting in hypoxemia. Norwogonin (NWG), a natural plant flavone, has shown potential anti-inflammatory and antioxidative effects. However, whether it could ameliorate sepsis-related ALI and the potential mechanism remains unknown.

This study aims to investigate the effects and underlying mechanisms of NWG in treating sepsis-related ALI.

Male Wistar rats (200-220 g) were used to establish sepsis-related ALI model via intraperitoneal injection of lipopolysaccharide (LPS). Vital signs and arterial blood gas analysis, HE and immunohistochemistry staining, dynamic visualization of the microcirculatory system to observe FITC-dextran leakage and leukocyte adhesion, ELISA assay of inflammatory cytokines, Evans Blue extravasation, measurement of total protein content in bronchoalveolar lavage fluid, determination of the Wet/Dry weight ratio, Western blot and RT-qPCR analysis were used to evaluate NWG's effects and the potential mechanism. Additionally, we employed network pharmacology and molecular docking to identify and evaluate the interaction between NWG and the key targets of ALI. Surface plasmon resonance and enzyme activity assay were utilized to confirm the direct interaction between NWG and the potential targets.

NWG administration improved the vital signs of LPS-stimulated rats. Exposure to LPS led to deteriorated arterial blood gas analysis, prominent lung morphology destruction, neutrophil and M1 macrophage infiltration, leukocyte adhesion, FITC-dextran leakage, elevated secretion of inflammatory cytokines, and aggravated lung edema. NWG intervention effectively mitigated these changes. Furthermore, NWG suppressed NF-κB/NLRP3 signaling and up-regulated endothelial junction proteins. Network pharmacology analysis and molecular docking identified five top key targets: MMP-9, AKT1, COX-2, Src and JAK-2. Western blot and RT-qPCR results confirmed that NWG inhibited the Src/AKT1/NF-κB signaling pathway, and down-regulated the levels of inflammatory factors. Surface plasmon resonance revealed the direct binding between NWG and AKT1, COX-2 and Src, rather than MMP-9. Enzyme activity assay demonstrated that NWG inhibited the activity of AKT1, COX-2 and Src.

NWG alleviated inflammation, restored pulmonary microvascular barrier function and improved LPS-induced ALI. These effects were mediated by inhibiting the Src/AKT1/NF-κB signaling pathway through direct targeting of Src, AKT1 and COX-2. Our study provided novel scientific evidence supporting the use of NWG in the treatment of ALI caused by sepsis.

Pneumonia is an acute respiratory infection of the lower respiratory tract. The effectiveness of the host immune response determines the severity of infection, or whether pneumonia occurs at all. The lungs house both innate and adaptive immune systems, which integrate their activities to provide host defense that eliminates microbes and prevents lower respiratory infection from becoming severe. Professional immune cells in the lung, like macrophages and lymphocytes, work with lung constituents, like epithelial cells and fibroblasts, to optimize antimicrobial defense. The dynamics of the immune response during infection and the immune components contributing to defense are influenced by prior experiences with respiratory pathogens, remodeling lung immunity in ways that improve responses against subsequent infections. This review covers how innate and adaptive immune activities coordinate inside the lung to provide integrated and effective immune resistance against respiratory pathogens.

Acute lung injury (ALI) is a difficult condition to manage, especially when it is complicated by bacterial sepsis. Hibifolin, a flavonoid glycoside, has anti-inflammatory properties that make it a potential treatment for ALI. However, more research is needed to determine its effectiveness in LPS-induced ALI. In this study, male ICR mice were treated with hibifolin before LPS-induced ALI. Protein content and neutrophil count in bronchoalveolar lavage (BAL) fluid were measured by BCA assay and Giemsa staining method, respectively. The levels of proinflammatory cytokines and adhesive molecules were detected by ELISA assay. The expression of NFκB p65 phosphorylation, IκB degradation, and Akt phosphorylation was assessed by western blot assay. Hibifolin pre-treatment significantly reduced pulmonary vascular barrier dysfunction and neutrophil infiltration into the BAL fluid in LPS-induced ALI mice. In addition, LPS-induced expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α) and adhesive molecules (ICAM-1, VCAM-1) within the BAL fluid were markedly reduced by hibifolin in LPS-induced ALI mice. More, hibifolin inhibited LPS-induced phosphorylation of NFκB p65, degradation of IκB, and phosphorylation of Akt in lungs with ALI mice. In conclusion, hibifolin shows promise in improving the pathophysiological features and proinflammatory responses of LPS-induced ALI in mice through the NFκB pathway and its upstream factor, Akt phosphorylation.

Neonatal acute respiratory distress syndrome (NARDS) is a severe and potentially life-threatening form of lung injury recently defined by the International Neonatal ARDS Consensus. It is marked by extensive lung inflammation and damage to the alveolar epithelium and vascular endothelium. NARDS can be triggered by direct inflammatory exposures, such as pneumonia and aspiration, and indirect exposures, including sepsis, necrotizing enterocolitis, and chorioamnionitis. This review provides clinicians and researchers with the latest insights on NARDS. We adopt a cross-disciplinary approach to discuss the diagnostic criteria, pathobiology, triggers, epidemiology, and treatments of NARDS. In addition, we summarize existing clinical studies and advanced preclinical models that help address current knowledge gaps. Future research should focus on standardizing the Montreux consensus definition of NARDS in preclinical and clinical studies, identifying biomarkers, developing prediction models, and exploring novel therapies for affected infants.

Acute hypoxemic respiratory failure (AHRF) is the leading cause of intensive care unit (ICU) admissions. Of patients with AHRF, 40 %-50 % will require invasive mechanical ventilation during their stay in the ICU, and 30 %-80 % will meet the Berlin Criteria for Acute Respiratory Distress Syndrome (ARDS). Rapid identification of the underlying cause of AHRF is necessary before initiating targeted treatment. Almost 10 % of patients with ARDS have no identified classic risk factors however, and the precise cause of AHRF may not be identified in up to 15 % of patients, particularly in cases of immunosuppression. In these patients, a multidisciplinary, comprehensive, and hierarchical diagnostic work-up is mandatory, including a detailed history and physical examination, chest computed tomography, extensive microbiological investigations, bronchoalveolar lavage fluid cytological analysis, immunological tests, and investigation of the possible involvement of pneumotoxic drugs.

Acute respiratory distress syndrome (ARDS), a progressive status of acute lung injury (ALI), is primarily caused by an immune-mediated inflammatory disorder, which can be an acute pulmonary complication of rheumatoid arthritis (RA). As a chronic inflammatory disease regulated by the immune system, RA is closely associated with the occurrence and progression of respiratory diseases. However, it remains elusive whether there are shared genes between the molecular mechanisms underlying RA and ARDS. The objective of this study is to identify potential shared genes for further clinical drug discovery through integrated analysis of bulk RNA sequencing datasets obtained from the Gene Expression Omnibus database, employing differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). The hub genes were identified through the intersection of common DEGs and WGCNA-derived genes. The Random Forest (RF) and least absolute shrinkage and selection operator (LASSO) algorithms were subsequently employed to identify key shared target genes associated with two diseases. Additionally, RA immune infiltration analysis and COVID-19 single-cell transcriptome analysis revealed the correlation between these key genes and immune cells. A total of 59 shared genes were identified from the intersection of DEGs and gene clusters obtained through WGCNA, which analyzed the integrated gene matrix of ALI/ARDS and RA. The RF and LASSO algorithms were employed to screen for target genes specific to ALI/ARDS and RA, respectively. The final set of overlapping genes (FCMR, ADAM28, HK3, GRB10, UBE2J1, HPSE, DDX24, BATF, and CST7) all exhibited a strong predictive effect with an area under the curve (AUC) value greater than 0.8. Then, the immune infiltration analysis revealed a strong correlation between UBE2J1 and plasma cells in RA. Furthermore, scRNA-seq analysis demonstrated differential expression of these nine target genes primarily in T cells and NK cells, with CST7 showing a significant positive correlation specifically with NK cells. Beyond that, transcriptome sequencing was conducted on lung tissue collected from ALI mice, confirming the substantial differential expression of FCMR, HK3, UBE2J1, and BATF. This study provides unprecedented evidence linking the pathophysiological mechanisms of ALI/ARDS and RA to immune regulation, which offers novel understanding for future clinical treatment and experimental research.

The objective of this study is to delineate the differential gene expression patterns of neutrophils in bronchoalveolar lavage fluid (BALF) from patients with sepsis and those experiencing progression to sepsis-induced acute respiratory distress syndrome (SI-ARDS). Additionally, we aim to comprehensively profile the transcriptomic landscape of neutrophils in BALF from patients with sepsis and SI-ARDS, particularly focusing on cases caused by specific bacterial pathogens.

Patients with confirmed sepsis (n = 14) or SI-ARDS (n = 11) were recruited. Besides, a control group consisting of patients with unrelated diseases (n = 7) who required bronchoscopy was also included (cohort 1). We collected the neutrophils in BALF from participants in cohort 1. To validate the identified differentially expressed genes (DEGs) and evaluate neutrophil apoptosis, an additional cohort (cohort 2) was recruited, consisting of 5 healthy controls, 10 patients with sepsis, and 10 patients with SI-ARDS. Peripheral blood neutrophils were collected from participants in cohort 2 for further analysis. DEGs between SI-ARDS patients and controls, sepsis patients and controls, as well as SI-ARDS patients and sepsis patients were identified. And, publicly available datasets were downloaded to compare with local results. Additionally, the DEGs were also identified between patients infected with drug-resistant Klebsiella pneumoniae and those infected with other bacterial pathogens. Furthermore, a third cohort (cohort 3) consisting of 57 sepsis patients and 46 SI-ARDS patients was recruited for investigating the prognostic significance of neutrophils in SI-ARDS.

In cohort 1, 8/14 of the septic patients and 6/11 of the SI-ARDS patients were affected by drug-resistant Klebsiella pneumonia. There were 9921 DEGs between sepsis patients and controls, 10,252 DEGs between SI-ARDS patients and controls, and 24 DEGs between SI-ARDS and sepsis patients in neutrophils from BALF. Notably, fatty acid-binding pro-tein 4 (FABP4) exhibited significant downregulation in SI-ARDS patients. In cohort 2, peripheral blood analysis confirmed consistent trends, demonstrating that FABP4 expression was decreased, which contributed to the attenuation of neutrophil apoptosis. And FABP4 inhibitor-induced apoptosis resistance was reversed by a phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) inhibitor. Furthermore, survival analysis revealed that SI-ARDS patients with low levels of neutrophil FABP4 expression exhibited poor survival. Additionally, 520 overlapping DEGs were identified between the sepsis and control group comparisons and the SI-ARDS and sepsis group comparisons. Among these overlapping DEGs, 85% were downregulated, predominantly targeting immune-related pathways, whereas a smaller subset was upregulated, mainly associated with metabolism. DEGs in neutrophils in BALF of SI-ARDS and controls notably overlapped with those in neutrophils in peripheral blood. Importantly, DEGs in sepsis/SI-ARDS caused by drug-resistant Klebsiella pneumoniae differed from DEGs in sepsis/SI-ARDS caused by other bacteria. Additionally, FABP4 expression consistently decreased, attenuating neutrophil apoptosis.

The downregulation of FABP4 in neutrophils was found to inhibit apoptosis through the activation of the PI3K/AKT signaling pathway. Importantly, the expression level of FABP4 in neutrophil emerged as a prognostic indicator for sepsis and SI-ARDS patients, suggesting its potential utility in clinical decision-making to address the challenges posed by this condition.

Background/Objectives: Acute respiratory distress syndrome (ARDS) is a life-threatening condition that frequently complicates high-risk cardiac surgery. We evaluated the circulating levels and transpulmonary gradient of intracellular proteins in patients at risk of developing ARDS after cardiac surgery using large scale-proteomics. Methods: We enrolled sixteen patients undergoing high-risk cardiac surgery, followed by planned ICU admission. Circulating levels of intracellular proteins were measured at the onset of the surgical procedure, at ICU admission (H0), and 24 h (H24) after surgery in blood samples simultaneously drawn from both the pulmonary artery and the left atrium. The primary endpoint was the occurrence of ARDS between ICU admission and the subsequent 48 h. Results: Among the studied proteins, the levels of intracellular lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were higher at H24 in the pulmonary artery in patients who developed ARDS (6.96; 95% CI [6.83-7.23]) compared to patients who did not (6.48; 95% CI [6.27-6.66]), p-value = 0.016. The transpulmonary gradient of intracellular LOX-1 levels was not significantly different between ARDS and non-ARDS patients at H0 but it was more negative at H24 in ARDS (-0.23; 95% CI [-0.27, -0.14]) than in non-ARDS patients (0.03; 95% CI [-0.14, 0.32]; p-value= 0.031), with a hazard ratio HR = 0.39 (95% CI [0.18-0.86]); p-value= 0.035. The area under the ROC curve of H24 LOX-1 transpulmonary gradient to predict ARDS occurrence was 0.83 (95% CI [0.62-1.00]). Conclusions: The transpulmonary gradient of intracellular LOX-1 levels was negatively associated with the occurrence of ARDS within the first 48 h after high-risk cardiac surgery, suggesting that lung trapping of LOX-1 may be linked to postoperative ARDS.

CMTM3 is a member of the human chemokine-like factor superfamily. The mechanistic role of CMTM3 in acute respiratory distress syndrome (ARDS) is not known. This study investigated the role of CMTM3 in the progression of ARDS and its impact on the function of vascular endothelial cells.

ARDS modeling in human umbilical vascular endothelial cells (HUVECs) was performed by treating with lipopolysaccharide (LPS) or hypoxia/reoxygenation. We assessed CMTM3 expression levels in the LPS- and hypoxia/reoxygenation-stimulated HUVEC cells. Furthermore, we assessed the role of CMTM3 in the permeability function and inflammatory response of the vascular endothelial cells under ARDS conditions using HUVEC cells with CMTM3 overexpression(adCMTM3) or knockdown(shCMTM3). Concurrently, we generated CMTM3 knockout (CMTM3ko) mice and evaluated the differences in pulmonary vascular permeability, inflammatory lung injury, and survival rates between the CMTM3ko-ARDS and WT-ARDS model mice.

HUVECs stimulated with LPS and hypoxia/reoxygenation showed significantly higher CMTM3 expression compared to the control group (p<0.05). Compared with the adsham-HUVECs, adCMTM3-HUVECs stimulated with LPS and hypoxia/reoxygenation demonstrated significantly higher cellular permeability (p<0.05) as well as IL-6 and TNF-α expression levels (p<0.05). Conversely, shCMTM3-HUVECs stimulated with LPS and hypoxia/reoxygenation showed significantly reduced cellular permeability as well as IL-6 and TNF-α expression levels (p<0.05). In vivo ARDS modeling experiments demonstrated that CMTM3-knockout ARDS mice exhibited significantly higher survival rates (p=0.0194) as well as significantly reduced lung injury and pulmonary vascular permeability (p<0.05) compared to the wild-type ARDS mice.

These findings demonstrated that CMTM3 played a critical role in the development of ARDS by influencing permeability of the pulmonary vascular endothelial cells and lung inflammation. Therefore, CMTM3 is a potential therapeutic target in ARDS.

Acute lung injury (ALI) is a severe respiratory disorder associated with high morbidity and mortality. Lipopolysaccharide (LPS) is widely used to induce ALI in animal models. D-carvone, a natural monoterpene, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effects of D-carvone on LPS-induced ALI in rats. Thirty-six male rats were randomly divided into six groups (n = 6): control, D-carvone (10 mg/kg and 20 mg/kg p.o.), LPS (10 mg/kg E. coli lipopolysaccharide i.p.), and LPS + D-carvone (LPS with either 10 or 20 mg/kg D-carvone). D-carvone was administered orally once daily for 10 days. On day 10, sepsis was induced with LPS administration, and samples were collected after 6 h under deep anesthesia. LPS administration caused significant lung injury, as evidenced by increased histopathological scores, upregulation of pro-inflammatory markers (TLR4, IL-1β, TNF-α), and oxidative stress (increased MDA, decreased GSH and SOD). Treatment with D-carvone at both doses significantly attenuated these changes. D-carvone downregulated pro-inflammatory markers, upregulated anti-inflammatory (NRF2) and anti-apoptotic (Bcl-2) proteins, and reduced the levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8) in lung tissues. In conclusion, D-carvone protects against LPS-induced ALI in rats, possibly through its anti-inflammatory and antioxidant properties. These findings suggest that D-carvone could be a potential therapeutic candidate for preventing and treating ALI.

Acute respiratory distress syndrome (ARDS) is a critical pulmonary disorder with manifestations of pulmonary edema, inflammation, and impaired oxygenation. Establishing reliable animal ARDS models has been critical for investigating its mechanisms and for testing pharmacological interventions. The present study sought to induce a moderate ARDS model in New Zealand White rabbits with a model involving a mix of lipopolysaccharide (LPS), oleic acid (OA), and ventilation-induced lung injury (VILI). Four experimental groups were established: negative control (NC, n = 4), OA (OM, n = 6), LPS + OA (LOM, n = 6), and LPS + OA + VILI (LOV, n = 6). Throughout the modeling process, vital signs (MAP and HR), respiratory parameters (Cdyn), and hematological indices (WBC and P/F) were continuously monitored, and lung ultrasound was performed. After the experiment, bronchoalveolar lavage fluid (BALF) was collected to measure total protein content, and lung tissue samples were collected to determine the wet-to-dry (W/D) ratio. HE-stained lung tissue sections were prepared and scored according to the ATS guidelines for lung injury scoring. The LOV group showed the most severe lung injury, significantly decreasing MAP and Cdyn. Pathological and ultrasound scores were considerably higher in the LOV group compared to the OM and LOM groups (p < 0.05). The lung W/D ratio was significantly higher in the LOM (6.68 ± 0.56) and LOV (7.40 ± 0.56) groups compared to the NC group (5.20 ± 0.16) (p < 0.05). At T6, the PaO2/FiO2 ratio in the LOV group was ≤200 mmHg, significantly lower than that in the NC group (p < 0.05). Some rabbits in the OM and LOM groups also had PaO2/FiO2 ratios ≤200 mmHg, but the difference compared to the NC group was not statistically significant. In conclusion, this study established a novel moderate ARDS model in New Zealand White rabbits using LPS, OA, and VILI. The model demonstrates severe lung damage, pulmonary edema, and sustained hypoxemia, providing a basis for future research.

Objectives: There is a scarcity of pharmacological treatments that efficiently address lung injury in individuals experiencing acute respiratory distress syndrome (ARDS). Early inhaled corticosteroids and ipratropium may reduce pulmonary inflammation and injury of the lungs, minimizing the risk of ARDS. Method: This is a double-blinded randomized control trial conducted on patients at risk of ARDS. Patients were randomly allocated into two groups; the intervention group (63 patients) were administered aerosolized budesonide and ipratropium bromide, and the control group (56) were administered a placebo every eight hours for five days. Alteration in oxygen saturation divided by inspired oxygen (Fio2) (S/F) after five days was the primary outcome. Secondary outcomes included ARDS occurrence, mechanical ventilation (MV) requirement, hospital stay duration, and mortality rates. Results: Of the 604 screened, only 119 patients were included. The intervention group (63 patients) S/F ratio recovered versus the fall of the control group. Both groups had similar organ dysfunction and 28-day mortality. The intervention group had significantly (p < 0.001) fewer cases developing ARDS (9.5%) and MV (9.5%) than the control group (46.4% and 35.7%, respectively). Conclusions: The administration of inhaled budesonide and ipratropium bromide improved oxygenation, as assessed by the S/F ratio, and significantly reduced the rate of ARDS development and the requirement of MV versus the control group. Larger multi-center trials including diverse patient populations are needed to validate these results.

Acute respiratory distress syndrome (ARDS) is a heterogeneous condition with varying response to prone positioning. We aimed to identify subphenotypes of ARDS patients undergoing prone positioning using machine learning and assess their association with mortality and response to prone positioning.

In this retrospective observational study, we enrolled 353 mechanically ventilated ARDS patients who underwent at least one prone positioning cycle. Unsupervised machine learning was used to identify subphenotypes based on respiratory mechanics, oxygenation parameters, and demographic variables collected in supine position. The primary outcome was 28-day mortality. Secondary outcomes included response to prone positioning in terms of respiratory system compliance, driving pressure, PaO2/FiO2 ratio, ventilatory ratio, and mechanical power.

Three distinct subphenotypes were identified. Cluster 1 (22.9% of whole cohort) had a higher PaO2/FiO2 ratio and lower Positive End-Expiratory Pressure (PEEP). Cluster 2 (51.3%) had a higher proportion of COVID-19 patients, lower driving pressure, higher PEEP, and higher respiratory system compliance. Cluster 3 (25.8%) had a lower pH, higher PaCO2, and higher ventilatory ratio. Mortality differed significantly across clusters (p = 0.03), with Cluster 3 having the highest mortality (56%). There were no significant differences in the proportions of responders to prone positioning for any of the studied parameters. Transpulmonary pressure measurements in a subcohort did not improve subphenotype characterization.

Distinct ARDS subphenotypes with varying mortality were identified in patients undergoing prone positioning; however, predicting which patients benefited from this intervention based on available data was not possible. These findings underscore the need for continued efforts in phenotyping ARDS through multimodal data to better understand the heterogeneity of this population.

The progression of acute respiratory distress syndrome (ARDS) from its onset due to disease or trauma to either recovery or death is poorly understood. Currently, there are no generally accepted treatments aside from supportive care using mechanical ventilation. However, this can lead to ventilator-induced lung injury (VILI), which contributes to a 30 to 40% mortality rate. In this study, we develop and demonstrate a technique to quantify forms of energy transport and dissipation during mechanical ventilation to directly evaluate their relationship to VILI. A porcine ARDS model was used, with ventilation parameters independently controlling lung overdistension and alveolar/airway recruitment/derecruitment (RD). Hourly measurements of airflow, tracheal and esophageal pressures, respiratory system impedance, and oxygen transport were taken for six hours following lung injury to track energy transfer and lung function. The final degree of injury was assessed histologically. Total and dissipated energies were quantified from lung pressure-volume relationships and subdivided into contributions from airflow, tissue viscoelasticity, and RD. Only RD correlated with physiologic recovery. Despite accounting for a very small fraction (2 to 5%) of the total energy dissipation, RD is damaging because it occurs quickly over a very small area. We estimate power intensity of RD energy dissipation to be 100 W/m2, equivalent to 10% of the Sun's luminance at the Earth's surface. Minimizing repetitive RD events may thus be crucial for mitigating VILI.

The onset of sepsis frequently coincides with acute respiratory distress syndrome (ARDS), which constitutes a significant contributor to severe acid-base disturbances in septic patients. In the pathogenesis of sepsis, it conducts a crucial role. lysosomal metabolic disorders and immune imbalance conduct a pivotal role. Despite extensive research into the alterations in immune status during sepsis, few studies have been reported to thoroughly examine the association between lysosomes and sepsis. As a result, this study is predominantly Intended to delve into the link between lysosome-related genes and alterations in the lysosome in the immune microenvironment from the standpoint of bioinformatics in sepsis. The Registration Number was ChiCTR1900021261. Registration Date is 2019/02/04. Method Sepsis data source: Sepsis data was collected from previous clinical data and sequencing results (Originated from BGI Shenzhen Co., Ltd.) and the GO database was utilized for data collection of lysosome-related genes. Differential expression genes (DEGs) were screened on clinical sequencing data by employing IDEP 0.93 software subsequent to quality control. Afterwards, enrichment analysis was conducted by adopting Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co expression Network Analysis (WGCNA), followed by cross referencing of lysosomal genes to identify DEGs associated with lysosomes. GO and KEGG pathway analysis wereperformed subsequently. The genes obtained from PLSGs and WGCNA by Creating a PPI network entails the following steps: the points were intersected at first. Afterwards, CytoHubba and MCODE analysis were performed by utilizing cytoscape software. Next, the intersection was taken to confirm Hub gene sequences, and subsequently the central DEGs tightly associated with existing CTD scores. Notwithstanding the fact that the causes of sepsis are multifaceted, ARDS can often trigger the development of sepsis in numerous cases. Simultaneously, with an aim to predict transcription factor levels in the central nervous system, Cytoscape software was adopted DEGs and to find relevant target miRNAs in the miRWalk database, and a correlated regulatory network was established accordingly. The SEPSIS immune infiltration model was constructed by employing ImmuCellAI software. Afterwards, the association between DEGs and immune microenvironment abundance was constructed by adopting Spearman's method. Last but not least, it is worth noting that single-cell sequencing has been validated as a method to analyze hub gene expression in immune cells of sepsis patients, enabling the selection of key genes that are closely associated with predictive outcomes. Result When acute respiratory distress syndrome (ARDS) is present, the differentially expressed genes (DEGs) are implicated in lysosomal metabolism and the regulation of the immune microenvironment. Six hub DEGs were bound up with sepsis or was attributable to the examinations. On top of that, it was determined that the patients had acute respiratory distress syndrome. The associated immune analysis illustrated a remarkable augment in T cell infiltration in the immune microenvironment of sepsis, while the infiltration relative to DC was reduced at certain level. Positive correlations were found between the two by employing Spearman analysis between hub DEGs and the regulatory role of immune cells. Moreover, it was universally acknowledged that anti-inflammatory immune cells were responsible for the negative correlation. On the basis of single-cell sequencing, it has been determined that CTSO and HLA-DQA1 were expressed in immune cells in sepsis. Aside from that, the survival-death curve direction suggested that they could be utilized as core genes for predicting sepsis-related prognosis analysis. Conclusion An analysis of this study demonstrates the interaction between sepsis lysosome-related metabolism and changes by understanding the pathogenesis of immune cells in the microenvironment. On this basis, we can develop new clinical diagnostics and therapeutic approaches of sepsis and identifying drug targets. Nonetheless, ARDS and sepsis can differ simply by the difference in site of infection; as the etiology of numerous ARDS cases is quite complex, progression to sepsis can occur if infection exacerbates or other complications arise, meeting the diagnostic criteria of sepsis 3.0.

During acute respiratory distress syndrome (ARDS), delayed apoptosis of neutrophils and impaired efferocytosis of macrophages constitute two critical limiting steps, leading to secondary inflammatory storm and posing a significant threat to human health. However, due to the failure of previous single target-centric treatments to effectively address these two limiting steps in controlling the inflammatory storm, no available therapies are approved for ARDS treatment. Herein, inspired by spontaneous inflammation resolution, two kinds of Apoptosis and Efferocytosis Restored Nanoparticles (AER NPs) are proposed to overcome these two limiting steps for counteracting severe inflammatory storm. For the first limiting step, neutrophil-targeted apoptosis-restored nanoparticles (AR NPs) accelerated the programmed apoptosis of inflammatory neutrophils. The resolution of the first limiting step facilitated the accumulation of macrophage-targeted and efferocytosis-restored nanoparticles (ER NPs), thereby restoring macrophage efferocytosis and alleviating the second limiting step. The results indicated that after sequential treatment with AER NPs, recruited neutrophils decreased to 13.86%, and macrophage efferocytosis increased to 563.24%. AER NPs promoted inflammation resolution and established a self-healing virtuous loop by addressing the two limiting steps, ultimately effectively treating ARDS. This work suggests that a strategy inspired by inflammation resolution holds promise as a potential approach for advancing inflammation therapy.

Background Acute respiratory distress syndrome (ARDS) affects a significant proportion of ICU patients and has a high mortality rate. The inflammation of the alveolar-capillary membrane is pathognomonic and characterized by increased capillary permeability and pulmonary edema. A safe, readily available anti-inflammatory agent delivered directly to the lungs could be a promising therapeutic approach. All these properties apply to nebulized furosemide. Objectives The primary objective of this study is to analyze 28-day all-cause ICU mortality while the secondary objectives include assessing hospital mortality, ICU and hospital length of stay (LOS), ventilator-free days at 28 days, successful extubation rate, and adverse events. Methods A double-blind, placebo-controlled, parallel-arm superiority RCT using an intention-to-treat (ITT) analysis to assess whether nebulized furosemide reduces mortality in adult mechanically ventilated ARDS patients will be employed. Results The results of descriptive and inferential analyses will be tabulated, and the significant results will be presented.

Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality, characterized by significant clinical heterogeneity. This heterogeneity complicates treatment selection and patient inclusion in clinical trials. Therefore, the objective of this study is to identify physiological subphenotypes of ARDS using machine learning, and to determine ventilatory variables that can effectively discriminate between these subphenotypes in a bedside setting with high performance, highlighting potential utility for future clinical stratification approaches.

A retrospective cohort study was conducted using data from our ICU, covering admissions from 2017 to 2021. The study included 224 patients over 18 years of age diagnosed with ARDS according to the Berlin criteria and undergoing invasive mechanical ventilation (IMV). Data on physiological and ventilatory variables were collected during the first 24 h IMV. We applied machine learning techniques to categorize subphenotypes in ARDS patients. Initially, we employed the unsupervised Gaussian Mixture Classification Model approach to group patients into subphenotypes. Subsequently, we applied supervised models such as XGBoost to perform root cause analysis, evaluate the classification of patients into these subgroups, and measure their performance.

Our models identified two ARDS subphenotypes with significant clinical differences and significant outcomes. Subphenotype Efficient (n = 172) was characterized by lower mortality, lower clinical severity and presented a less restrictive pattern with better gas exchange compared to Subphenotype Restrictive (n = 52), which showed the opposite. The models demonstrated high performance with an area under the ROC curve of 0.94, sensitivity of 94.2% and specificity of 87.5%, in addition to an F1 score of 0.85. The most influential variables in the discrimination of subphenotypes were distension pressure, respiratory frequency and exhaled carbon dioxide volume.

This study presents an approach to improve subphenotype categorization in ARDS. The generation of clustering and prediction models by machine learning involving clinical, ventilatory mechanics, and gas exchange variables allowed for more accurate stratification of patients. These findings have the potential to optimize individualized treatment selection and improve clinical outcomes in patients with ARDS.