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AbstractBackgroundMethodsResultsConclusionsThe abnormality of the immune system caused by infection is a contributor to the organ dysfunctions associated with sepsis. The balance between Th17/Treg cells is essential for maintaining immune homeostasis. Bergapten is a natural furocoumarin and has been reported to alleviate the Th17/Treg imbalance. Here, we explored the effects of bergapten on the inflammation and immune state in mouse models of sepsis.The model was established using the cecal ligation and puncture method. Mice were administered 30 mg/kg bergapten. Histological examination, RT-qPCR, enzyme-linked immunosorbent assay, immunoblotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to evaluate the effects of bergapten in vivo.Bergapten ameliorated lung damage, reduced lung wet/dry weight ratio, inhibited myeloperoxidase activity, and reduced inflammatory cell infiltration. Bergapten also restrained sepsis-induced inflammation via inhibition of inflammatory cytokines and NF-κB signaling. These effects were accompanied by the restored Th17/Treg balance induced by bergapten. Bergapten decreased the number of Th17 cells and elevated the number of Tregs, and this effect was mediated by the signal transducer and activator of transcription 5 (STAT5)/Forkhead box P3 (Foxp3) and STAT3/retinoid-related orphan receptor-γt (RORγt) pathways.Bergapten exerted anti-inflammatory effects in acute lung injury by improving the Th17/Treg balance, which suggested a potential of bergapten as an immunomodulatory drug treating sepsis-associated diseases. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S), as a key gas signaling molecule, plays an important role in regulating various diseases, with appropriate concentrations providing antioxidative, anti-inflammatory, and anti-apoptotic effects. The specific role of H2S in acute hypoxic injury remains to be clarified. This study focuses on the H2S donor sodium hydrosulfide (NaHS) and explores its protective effects and mechanisms against acute hypoxic lung injury. First, various mouse hypoxia models were established to evaluate H2S's protection in hypoxia tolerance. Next, a rat model of acute lung injury (ALI) induced by hypoxia at 6500 m above sea level for 72 h was created to assess H2S's protective effects and mechanisms. Evaluation metrics included blood gas analysis, blood routine indicators, lung water content, and lung tissue pathology. Additionally, LC-MS/MS and bioinformatic analyses were combined in performing quantitative proteomics on lung tissues from the normoxic control group, the hypoxia model group, and the hypoxia model group with NaHS treatment to preliminarily explore the protective mechanisms of H2S. Further, enzyme-linked immunosorbent assays (ELISA) were used to measure oxidative stress markers and inflammatory factors in rat lung tissues. Lastly, Western blot analysis was performed to detect Nrf2, HO-1, P-NF-κB, NF-κB, HIF-1α, Bcl-2, and Bax proteins in lung tissues. Results showed that H2S exhibited significant anti-hypoxic effects in various hypoxia models, effectively modulating blood gas and blood routine indicators in ALI rats, reducing pulmonary edema, improving lung tissue pathology, and alleviating oxidative stress, inflammatory responses, and apoptosis levels. [ABSTRACT FROM AUTHOR]

Background: Numerous diseases-related acute lung injury (ALI) contributed to high mortality. Currently, the therapeutic effect of ALI was still poor. The detailed mechanism of ALI remained elusive and this study aimed to elucidate the mechanism of ALI. Method: This study was performed to expose the molecular mechanisms of AMPK/Nrf2 pathway regulating oxidative stress in LPS-induced AMI mice. The mouse ALI model was established via intraperitoneal injection of LPS, then the lung tissue and blood samples were obtained, followed by injection with Dimethyl fumarate (DMF). Finally, Western blot, HE staining, injury score, lung wet/dry ratio, reactive oxygen species (ROS) and ELISA were used to elucidate the mechanism of AMPK/Nrf2 pathway in LPS -induced acute lung injury by mediating oxidative stress. Results: The lung tissue injury score was evaluated, showing higher scores in the model group compared to the AMPK activator and control groups. DCFH-DA indicated that LPS increased ROS production, while AMPK activator DMF reduced it, with the model group exhibiting higher ROS levels than the control and AMPK activator groups. The lung wet/dry ratio was also higher in the model group. Western blot analysis revealed LPS reduced AMPK and Nrf2 protein levels, but DMF reversed this effect. ELISA results showed elevated IL-6 and IL-1β levels in the model group compared to the AMPK activator and control groups.Conclusion: Conclusion: Activating the AMPK/Nrf2 pathway can improve LPS-induced acute lung injury by down-regulation of the oxidative stress and corresponding inflammatory factor level. [ABSTRACT FROM AUTHOR]

Introduction: Reducing cardiopulmonary bypass (CPB) induced inflammatory injury is a potentially important strategy for children undergoing multiple operations for single ventricle palliation. We sought to characterize the soluble receptor for advanced glycation end products (sRAGE), a protein involved in acute lung injury and inflammation, in pediatric patients with congenital heart disease and hypothesized that patients undergoing single ventricle palliation would have higher levels of sRAGE following bypass than those with biventricular physiologies. Methods: This was a prospective, observational study of children undergoing CPB. Plasma samples were obtained before and after bypass. sRAGE levels were measured and compared between those with biventricular and single ventricle heart disease using descriptive statistics and multivariate analysis for risk factors for lung injury. Results: sRAGE levels were measured in 40 patients: 19 with biventricular and 21 with single ventricle heart disease. Children undergoing single ventricle palliation had a higher factor and percent increase in sRAGE levels when compared to patients with biventricular circulations (4.6 vs. 2.4, p = 0.002) and (364% vs. 181%, p = 0.014). The factor increase in sRAGE inversely correlated with the patient's preoperative oxygen saturation (Pearson correlation (r) = −0.43, p = 0.005) and was positively associated with red blood cell transfusion (coefficient = 0.011; 95% CI: 0.004, 0.017; p = 0.001). Conclusions: Children with single ventricle physiology have greater increase in sRAGE following CPB as compared to children undergoing biventricular repair. Larger studies delineating the role of sRAGE in children undergoing single ventricle palliation may be beneficial in understanding how to prevent complications in this high-risk population. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is caused by a variety of intrapulmonary and extrapulmonary factors and is associated with high morbidity and mortality. Oxidative stress is an important part of the pathological mechanism of ALI. Ferroptosis is a mode of programmed cell death distinguished from others and characterized by iron-dependent lipid peroxidation. This article reviews the metabolic regulation of ferroptosis, its role in the pathogenesis of ALI, and the use of ferroptosis as a therapeutic target regarding the pharmacological treatment of ALI. [ABSTRACT FROM AUTHOR]

ALI/ARDS can be a pulmonary manifestation of a systemic inflammatory response or a result of overexpression of the body's normal inflammatory response involving various effector cells, cytokines, and inflammatory mediators, which regulate the body's immune response through different signalling pathways. Forkhead box transcription factors are evolutionarily conserved transcription factors that play a crucial role in various cellular processes, such as cell cycle progression, proliferation, differentiation, migration, metabolism, and DNA damage response. Transcription factors control protein synthesis by regulating gene transcription levels, resulting in diverse biological outcomes. The Fox family plays a role in activating or inhibiting the expression of various molecules related to ALI/ARDS through phosphorylation, acetylation/deacetylation, and control of multiple signalling pathways. An in-depth analysis of the integrated Fox family's role in ALI/ARDS can aid in the development of potential diagnostic and therapeutic targets for the condition. [ABSTRACT FROM AUTHOR]

Background: Free fatty acids (FFAs) are established risk factors for various cardiovascular and metabolic disorders. Elevated FFAs can trigger inflammatory response, which may be associated with the occurrence of acute respiratory distress syndrome (ARDS) in cardiac surgery. In this prospective study, we aimed to investigate the association between circulating FFA and the incidence of ARDS, as well as the length of ICU stay, in patients undergoing off-pump coronary artery bypass grafting (CABG). Methods: We conducted a single-center, prospective, observational study among patients undergoing off-pump CABG. The primary endpoint was the occurrence of ARDS within 6 days after off-pump CABG. Serum FFA were measured at baseline and 24 h post-procedure, and the difference (Δ-FFA) was calculated. Results: A total of 180 patients were included in the primary analysis. The median FFA was 2.3 mmol/L (quartile 1 [Q1]–Q3, 1.4–3.2) at baseline and 1.5 mmol/L (Q1–Q3, 0.9–2.3) 24 h after CABG, with a Δ-FFA of 0.6 mmol/L (Q1–Q3, -0.1 to 1.6). Patients with elevated Δ-FFA levels had a significantly higher ARDS occurrence (55.6% vs. 22.2%; P < 0.001). Elevated Δ-FFA after off-pump CABG correlated with a significantly lower PaO2/FiO2 ratio, prolonged mechanical ventilation, and extended length of ICU stay. The area under the curve (AUC) of Δ-FFA for predicting ARDS (AUC, 0.758; 95% confidence interval, 0.686–0.831) significantly exceeded the AUC of postoperative FFA (AUC, 0.708; 95% CI 0.628–0.788; P < 0.001). Conclusions: Elevated Δ-FFA levels correlated with ARDS following off-pump CABG. Monitoring FFA may assist in identifying high-risk patients for ARDS, facilitating timely interventions to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Despite the recommendation for lung-protective mechanical ventilation (LPMV) in pediatric acute respiratory distress syndrome (PARDS), there is a lack of robust supporting data and variable adherence in clinical practice. This study evaluates the impact of an LPMV protocol vs. standard care and adherence to LPMV elements on mortality. We hypothesized that LPMV strategies deployed as a pragmatic protocol reduces mortality in PARDS. DESIGN: Multicenter prospective before-and-after comparison design study. SETTING: Twenty-one PICUs. PATIENTS: Patients fulfilled the Pediatric Acute Lung Injury Consensus Conference 2015 definition of PARDS and were on invasive mechanical ventilation. INTERVENTIONS: The LPMV protocol included a limit on peak inspiratory pressure (PIP), delta/driving pressure (DP), tidal volume, positive end-expiratory pressure (PEEP) to FIO2 combinations of the low PEEP acute respiratory distress syndrome network table, permissive hypercarbia, and conservative oxygen targets. MEASUREMENTS AND MAIN RESULTS: There were 285 of 693 (41[middle dot]1%) and 408 of 693 (58[middle dot]9%) patients treated with and without the LPMV protocol, respectively. Median age and oxygenation index was 1.5 years (0.4-5.3 yr) and 10.9 years (7.0-18.6 yr), respectively. There was no difference in 60-day mortality between LPMV and non-LPMV protocol groups (65/285 [22.8%] vs. 115/406 [28.3%]; p = 0.104). However, total adherence score did improve in the LPMV compared to non-LPMV group (57.1 [40.0-66.7] vs. 47.6 [31.0-58.3]; p < 0[middle dot]001). After adjusting for confounders, adherence to LPMV strategies (adjusted hazard ratio, 0.98; 95% CI, 0.97-0.99; p = 0.004) but not the LPMV protocol itself was associated with a reduced risk of 60-day mortality. Adherence to PIP, DP, and PEEP/FIO2 combinations were associated with reduced mortality. CONCLUSIONS: Adherence to LPMV elements over the first week of PARDS was associated with reduced mortality. Future work is needed to improve implementation of LPMV in order to improve adherence. [ABSTRACT FROM AUTHOR]

Objective: Sepsis can have severe implications on lung function, leading to acute lung injury (ALI), a major contributor to sepsis-related mortality. Anisodamine hydrobromide (Ani HBr), a bioactive constituent derived from the root of Scopolia tangutica Maxim, a plant endemic to China, has demonstrated efficacy in treating septic shock. We aim to explore whether Ani HBr can alleviate sepsis-triggered ALI and elucidate the fundamental mechanisms involved. Materials and method: The protective effects of Ani HBr were assessed in two models: in vitro, lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and in vivo, cecal ligation puncture (CLP)-induced sepsis. To measure the cell viability of RAW264.7 cells after Ani HBr treatment, we used the CCK-8 assay. We quantified the levels of pro-inflammatory cytokines expression using ELISA. We also measured the expression of pyrotosis indicators by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence. Results: Our study demonstrates that Ani HBr can alleviate pulmonary edema, bleeding, and excessive inflammation induced by CLP. Additionally, it exhibits protective effects against cytotoxicity induced by LPS in RAW264.7 macrophage cells. Furthermore, Ani HBr downregulates the mRNA and protein levels of NLRP3, Caspase-1, GSDMD, IL-18, and IL-1β in both animal models and cell cultures, thereby inhibiting pyroptosis in a similar mechanism to AC-YVAD-CMK (AYC)'s blockade of Caspase-1. Moreover, Ani HBr suppresses the production and release of proinflammatory cytokines. Conclusion: These findings suggest that Ani HBr could serve as a protective agent against sepsis-induced ALI by suppressing pyroptosis. [ABSTRACT FROM AUTHOR]

Background: Pulmonary surfactant (PS) plays an important role in the treatment of sepsis-induced acute lung injury (ALI). Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, improves the secretion and function of PS in ALI, but the underlying mechanism remains unknown. This study aimed to investigate how liraglutide regulates PS secretion in ALI. Methods: C57BL/6 mice were injected subcutaneously with normal saline containing different concentrations of liraglutide after the establishment of the ALI model. MLE-12 cells were treated with liraglutide after LPS stimulation. The survival rate of mice, wet/dry weight ratio, inflammatory factors in bronchoalveolar lavage fluid (BALF), pulmonary injury, and apoptosis were analyzed. Cell viability, proliferation, apoptosis, the expression of SP-A, SP-B, and expression of autophagy-related proteins in cells were measured. Results: ALI mice showed reduced pulmonary injury, less apoptosis, and less inflammation compared to the controls. Liraglutide prolonged survival, decreased the wet/dry weight ratio, reduced inflammatory responses, and attenuated pulmonary edema compared with the ALI group. Moreover, LPS-induced cell damage and reduction of SP-A and SP-B expression were markedly reversed by liraglutide in MLE-12 cells. Furthermore, the protective effects of liraglutide were reversed by rapamycin. Conclusion: Liraglutide alleviate sepsis-induced ALI by inhibiting autophagy and regulating PS. [ABSTRACT FROM AUTHOR]

Background: Exposure to a hypobaric hypoxic environment at high altitudes can lead to lung injury. In this study, we aimed to determine whether curcumin (Cur) could improve lung barrier function and protect against high-altitude-associated acute lung injury. Methods: Two hundred healthy rats were randomly divided into standard control, high-altitude control (HC), salidroside (40 mg/kg, positive control), and Cur (200 mg/kg) groups. Each group was further divided into five subgroups. Basic vital signs, lung injury histopathology, routine blood parameters, plasma lactate level, and arterial blood gas indicators were evaluated. Protein and inflammatory factor (tumor necrosis factor α (TNF-α), interleukin [IL]-1β, IL-6, and IL-10) concentrations in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method and enzyme-linked immunosorbent assay, respectively. Inflammation-related and lung barrier function-related proteins were analyzed using immunoblotting. Results: Cur improved blood routine indicators such as hemoglobin and hematocrit and reduced the BALF protein content and TNF-α, IL-1β, and IL-6 levels compared with those in the HC group. It increased IL-10 levels and reduced pulmonary capillary congestion, alveolar hemorrhage, and the degree of pulmonary interstitial edema. It increased oxygen partial pressure, oxygen saturation, carbonic acid hydrogen radical, and base excess levels, and the expression of zonula occludens 1, occludin, claudin-4, and reduced carbon dioxide partial pressure, plasma lactic acid, and the expression of phospho-nuclear factor kappa. Conclusions: Exposure to a high-altitude environment for 48 h resulted in severe lung injury in rats. Cur improved lung barrier function and alleviated acute lung injury in rats at high altitudes. Highlights: • Curcumin (Cur) improves lung barrier function under high-altitude stress in rats • Cur mitigated acute lung injury under high-altitude stress • Cur improved hemoglobin and hematocrit levels under high-altitude stress • Cur reduced bronchoalveolar lavage fluid protein content under high-altitude stress • Cur reduced inflammatory factor TNF-α, IL-α, IL-6 levels under high-altitude stress [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) poses a significant and escalating medical challenge, where precise diagnosis and timely intervention hold utmost importance in halting its deterioration. Nevertheless, persistent obstacles arise from the lack of agents proficient in both real‐time diagnosis and efficient mitigation of ALI. Here, a biocatalytic and second near‐infrared (NIR‐II) fluorescence‐illuminating nanoplatform is designed to simultaneously facilitate real‐time monitoring and robust inflammation alleviation in ALI. The study first develops a new aggregation‐induced emission luminogen with trifluoromethyl substitutions, which simultaneously increase NIR‐II emission wavelength and fluorescence brightness. The molecular probe is further integrated into biocatalytic hollow ceria nanostructures, and cloaked with pre‐activated macrophage membranes for targeted inflammation intervention. Upon inhalation administration in ALI mice, the theranostic nanoagents leverage the bright NIR‐II emission and active inflammation‐tropic properties for in vivo sensitive NIR‐II imaging of ALI, which also facilitates real‐time tracking of the nanoagents' distribution and dynamic fate within pneumonia milieu. Concurrently, the catalytic prowess of the nanoplatforms efficaciously scavenges excess reactive oxygen species, dampens proinflammatory cytokines, and promotes macrophage repolarization, substantially alleviating acute lung damage. The multifaceted nanoplatform integrates NIR‐II bioimaging with nanocatalysis‐mediated immunoregulation, offering a versatile and promising approach for addressing the intricate challenges posed by acute inflammation diseases. [ABSTRACT FROM AUTHOR]

Skeletal muscle dysfunction in critical illnesses leaves survivors weak and functionally impaired. Macrophages infiltrate muscles; however, their functional role is unclear. We aim to examine muscle leukocyte composition and the effect of macrophages on muscle mass and function in the murine acute lung injury (ALI)‐associated skeletal muscle wasting model. We performed flow cytometry of hindlimb muscle to identify myeloid cells pre‐injury and time points up to 29 days after intratracheal lipopolysaccharide ALI. We evaluated muscle force and morphometrics after systemic and intramuscular clodronate‐induced macrophage depletions between peak lung injury and recovery (day 5–6) versus vehicle control. Our results show muscle leukocytes changed over ALI course with day 3 neutrophil infiltration (130.5 ± 95.6cells/mg control to 236.3 ± 70.6cells/mg day 3) and increased day 10 monocyte abundance (5.0 ± 3.4%CD45+CD11b+ day 3 to 14.0 ± 2.6%CD45+CD11b+ day 10, p = 0.005). Although macrophage count did not significantly change, pro‐inflammatory (27.0 ± 7.2% day 3 to 7.2 ± 3.8% day 10, p = 0.02) and anti‐inflammatory (30.5 ± 11.1% day 3 to 52.7 ± 9.7% day 10, p = 0.09) surface marker expression changed over the course of ALI. Macrophage depletion following peak lung injury increased muscle mass and force generation. These data suggest muscle macrophages beyond peak lung injury limit or delay muscle recovery. Targeting macrophages could augment muscle recovery following lung injury. [ABSTRACT FROM AUTHOR]

This study describes a complex human in vitro model for evaluating anti‐inflammatory drug response in the alveoli that may contribute to the reduction of animal testing in the pre‐clinical stage of drug development. The model is based on the human alveolar epithelial cell line Arlo co‐cultured with macrophages differentiated from the THP‐1 cell line, creating a physiological biological microenvironment. To mimic the three‐dimensional architecture and dynamic expansion and relaxation of the air‐blood‐barrier, they are grown on a stretchable microphysiological lung‐on‐chip. For validating the in vitro model, three different protocols have been developed to demonstrate the clinically established anti‐inflammatory effect of glucocorticoids to reduce certain inflammatory markers after different pro‐inflammatory stimuli: (1) an inflammation caused by bacterial LPS (lipopolysaccharides) to simulate an LPS‐induced acute lung injury measured best with cytokine IL‐6 release; (2) an inflammation caused by LPS at ALI (air‐liquid interface) to investigate aerosolized anti‐inflammatory treatment, measured with chemokine IL‐8 release; and (3) an inflammation with a combination of human inflammatory cytokines TNFα and IFNγ to simulate a critical cytokine storm leading to epithelial barrier disruption, where the eventual weakening or protection of the epithelial barrier can be measured. In all cases, the presence of macrophages appeared to be crucial to mediating inflammatory changes in the alveolar epithelium. LPS induction led to inflammatory changes independently of stretch conditions. Dynamic stretch, emulating breathing‐like mechanics, was essential for in vitro modeling of the clinically relevant outcome of epithelial barrier disruption upon TNFα/IFNγ‐induced inflammation. [ABSTRACT FROM AUTHOR]

Background: Transfusion-related acute lung injury (TRALI) is a rare life-threatening complication of blood product transfusion. Intravenous immunoglobulin (IVIG)-related TRALI is scarcely reported. Case presentation: A 63-year-old male patient suffering from multiple sclerosis treated with half-yearly rituximab infusions, was hospitalized due to dry cough, daily fever and shivering for seven days despite antibiotic therapy. Because of the history of COVID-19 one month prior without the symptoms having improved since, persistent bilateral multifocal areas of ground glass opacities in chest computed tomography and positive SARS-CoV-2 PCR from bronchoalveolar lavage with a cycling time of 30.1 COVID-19 due to long-shedding SARS-CoV-2 under immunosuppression with rituximab was diagnosed. He received treatment with nirmatrelvir und ritonavir and because of diagnosed IgG deficiency additionally a single dose of 20 g IVIG. During the IVIG infusion, the patient acutely developed tachycardia, hypotension, fever, chills, and hypoxemic respiratory failure due to pulmonary edema. TRALI was promptly diagnosed, and the patient was transferred to the intensive care unit for non-invasive ventilation for less than 24 h. The patient was discharged home from regular ward 72 h later in a good general condition and no remaining symptoms of TRALI. Conclusion: IVIG-related TRALI is a rare but life-threating condition and prompt recognition is lifesaving. Due to an increased use of IVIG not only in long-shedding SARS-CoV-2, an increase of TRALI incidence is expected. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC)‐derived extracellular vesicles (EVs) have shown anti‐inflammatory potential in multiple inflammatory diseases. In the March 2022 issue of the Journal of Extracellular Vesicles, it was shown that EVs from human MSCs can suppress severe acute respiratory distress syndrome, coronavirus 2 (SARS‐CoV‐2) replication and can mitigate the production and release of infectious virions. We therefore hypothesized that MSC‐EVs have an anti‐viral effect in SARS‐CoV‐2 infection in vivo. We extended this question to ask whether also other respiratory viral infections could be treated by MSC‐EVs. Adipose stem cell‐derived EVs (ASC‐EVs) were isolated using tangential flow filtration from conditioned media obtained from a multi‐flask cell culture system. The effects of the ASC‐EVs were tested in Vero E6 cells in vitro. ASC‐EVs were also given i.v. to SARS‐CoV‐2 infected Syrian Hamsters, and H1N1 influenza virus infected mice. The ASC‐EVs attenuated SARS‐CoV‐2 virus replication in Vero E6 cells and reduced body weight and signs of lung injury in infected Syrian hamsters. Furthermore, ASC‐EVs increased the survival rate of influenza A‐infected mice and attenuated signs of lung injury. In summary, this study suggests that ASC‐EVs can have beneficial therapeutic effects in models of virus‐infection‐associated acute lung injury and may potentially be developed to treat lung injury in humans. [ABSTRACT FROM AUTHOR]

Introduction: Acute lung injury (ALI) is a critical and lethal medical condition. This syndrome is characterized by an imbalance in the body's oxidation stress and inflammation. Linoleic acid (LA), a polyunsaturated fatty acid, has been extensively studied for its potential health benefits, including anti‐inflammatory and antioxidant activities. However, the therapeutic effects of LA on ALI remain unexplored. Methods: Lipopolysaccharide (LPS), found in gram‐negative bacteria's outer membrane, was intraperitoneally injected to induce ALI in mice. In vitro model was established by LPS stimulation of mouse lung epithelial 12 (MLE‐12) cells. Results: LA treatment demonstrated a significant amelioration in LPS‐induced hypothermia, poor state, and pulmonary injury in mice. LA treatment resulted in a reduction in the concentration of bronchoalveolar lavage fluid (BALF) protein and an increase in myeloperoxidase (MPO) activity in LPS‐induced mice. LA treatment reduced the generation of white blood cells. LA treatment reduced cell‐free (cfDNA) release and promote adenosine triphosphate (ATP) production. LA increased the levels of superoxide dismutase (SOD) and glutathione (GSH) but decreased the production of malondialdehyde (MDA). LA treatment enhanced mitochondrial membrane potential. LA attenuated LPS‐induced elevations of inflammatory cytokines in both mice and cells. Additionally, LA exerted its protective effect against LPS‐induced damage through activation of the peroxisome proliferator‐activated receptor γ coactivator l alpha (PGC‐1α)/nuclear respiratory factor 1 (NRF1)/transcription factor A of the mitochondrion (TFAM) pathway. Conclusion: LA may reduce inflammation and stimulate mitochondrial biogenesis in ALI mice and MLE‐12 cells. [ABSTRACT FROM AUTHOR]

Emerging evidence has reported that acute lung injury (ALI), characterized by inflammation and oxidative stress in airway epithelium, is regulated by programmed cell death. Ferroptosis, a regulated form of cell death spurred by uncontrolled lipid peroxidation, has been proven to implicate various diseases. Inhibiting ferroptosis represents a feasible strategy for ALI through the suppression of lipid peroxidation, while the mechanism remains to be further elucidated. Here, we identified Sequestosome 1 (SQSTM1) as a negative regulator of airway epithelium ferroptosis during ALI. SQSTM1 knockdown cells manifested higher sensitivity to ferroptosis. Mechanistically, SQSTM1 was found to directly interact with vitamin D receptor (VDR) through its nuclear receptor (NR) box motif, facilitating its nuclear translocation and initiating autophagy at the transcriptional level. To further validate these findings, an in vivo preventive model utilizing spermidine, a proven inducer of SQSTM1 was established. The results consistently demonstrated that spermidine supplementation significantly induced SQSTM1 and ameliorated ALI by mitigating airway epithelial ferroptosis. Notably, these effects were abrogated in the absence of SQSTM1. Taken together, this study identified SQSTM1 as a negative regulator of airway epithelium ferroptosis in a VDR-mediated autophagy manner, making it a potential therapeutic target for the treatment of ALI. [Display omitted] • SQSTM1 was identified as a potential target for acute lung injury treatment. • SQSTM1 inhibited ferroptosis by directly interacting with VDR through its NR box motif. • Spermidine was evidenced to be beneficial to both LPS- and CS-induced acute lung injury. • Spermidine upregulated SQSTM1 and inhibited ferroptosis to improve acute lung injury. [ABSTRACT FROM AUTHOR]

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is intricately involved in modulating the inflammatory response in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Nevertheless, the myeloid PTEN governing Hippo-YAP pathway mediated oxidative stress and inflammation in lipopolysaccharide (LPS)-induced ALI remains to be elucidate. The floxed Pten (PtenFL/FL) and myeloid-specific Pten knockout (PtenM−KO) mice were intratracheal instill LPS (5 mg/kg) to establish ALI, then Yap siRNA mix with the mannose-conjugated polymers was used to knockdown endogenous macrophage YAP in some PtenM−KO mice before LPS challenged. The bone marrow-derived macrophages (BMMs) from PtenFL/FL and PtenM−KO mice were obtained, and BMMs were transfected with CRISPR/Cas9-mediated glycogen synthase kinase 3 Beta (GSK3β) knockout (KO) or Yes-associated protein (YAP) KO vector subjected to LPS (100 ng/ml) challenged or then cocultured with MLE12 cells. Here, our findings demonstrate that myeloid-specific PTEN deficiency exerts a protective against LPS-induced oxidative stress and inflammation dysregulated in ALI model. Moreover, ablation of the PTEN-YAP axis in macrophages results in reduced nuclear factor-E2-related factor-2 (NRF2) expression, a decrease in antioxidant gene expression, augmented levels of free radicals, lipid and protein peroxidation, heightened generation of pro-inflammatory cytokines, ultimately leading to increased apoptosis in MLE12 cells. Mechanistically, it is noteworthy that the deletion of myeloid PTEN promotes YAP translocation and regulates NRF2 expression, alleviating LPS-induced ALI via the inhibition of GSK3β and MST1 binding. Our study underscores the crucial role of the myeloid PTEN-YAP-NRF2 axis in governing oxidative stress and inflammation dysregulated in ALI, indicating its potential as a therapeutic target for ALI. [Display omitted] • Myeloid Pten deficiency activate YAP translocation protect against in LPS-induced ALI. • The modulation of the Hippo-YAP pathway by PTEN necessitates the interaction between GSK3β and MST1. • Macrophage PTEN-YAP axis modulates the NRF2 expression. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa infection causes pneumonia and sepsis. Previous research found that X‐ray radiation can induce P. aeruginosa to release outer membrane vesicles (OMVs) of relatively consistent sizes. This study found that OMVs derived from X‐ray‐irradiated P. aeruginosa can significantly inhibit lung leakage, inflammatory cell infiltrating into lung, and the production of pro‐inflammatory cytokines, IL‐1β and TNFα caused by P. aeruginosa infection under preventive and therapeutic administration conditions. Under the same conditions, OMVs also significantly alleviated pathological characteristics of lung injury, including pulmonary edema, pulmonary hemorrhage, and alveolar wall thickening. OMVs also significantly reduced bacterial burdens in peritoneal cavity, accompanied by a reduction in the number of viable bacteria capable of forming bacterial colonies. Pretreating macrophages and neutrophils with OMVs enhances their bactericidal ability. When bacteria were cocultured with treated cells, the number of viable bacteria capable of forming bacterial colonies was significantly reduced. OMVs themselves have not been shown to cause any lung injury or affect bacterial viability. Therefore, OMVs derived from X‐ray‐irradiated P. aeruginosa may not only be applied in prevention and treatment of diseases associated with P. aeruginosa infection, but also served as an excellent vaccine development platform. [ABSTRACT FROM AUTHOR]

Background: Finding a dead body in water raises an issue concerning determining the cause of death as drowning because of the complex pathophysiology of drowning. In addition, the corpse may be submersed postmortem. Objective: Evaluate the role of oxidative stress markers and NF-KB/iNOS inflammatory pathway as diagnostic biomarkers in drowning and whether they could differentiate freshwater from saltwater drowning. Methods: This study included forty-five adult male albino rats classified into five groups: control group (C), Freshwater-drowned group (FD), Freshwater postmortem submersion group (FPS), saltwater-drowned group (SD), and saltwater postmortem submersion group (SPS). After the autopsy, the rats' lungs in each group were prepared for histological, immunohistochemical (caspase 3, TNF-α, NF-kB, COX-2 & iNOS), biochemical studies; MDA, NOx, SOD, GSH, VCAM-1, COX-2; and RT-PCR for the relative quantification of NF-kB and iNOS genes expression. Results: Lung oxidative markers were significantly affected in drowned groups than in postmortem submersion groups. Inflammatory pathway markers were also significantly increased in the drowned groups, with concern that all markers were significantly affected more in saltwater than in freshwater drowned group. Conclusions: It is concluded that the tested markers can be used accurately in diagnosing drowning and differentiating it from postmortem submersion with a better understanding of the mechanism of death in drowning as both mechanisms, inflammatory and oxidative stress, were revealed and involved. [ABSTRACT FROM AUTHOR]

Higher levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a TLR4 agonist, are associated with poor clinical outcomes in sepsis-induced acute lung injury (ALI). Little is known regarding the mechanisms by which eNAMPT is involved in ALI. Our recent work has identified a crucial role for mitochondrial dysfunction in ALI. Thus, this study aimed to determine if eNAMPT-mediated inflammatory injury is associated with the loss of mitochondrial function. Our data show that eNAMPT disrupted mitochondrial bioenergetics. This was associated with cytoskeleton remodeling and the loss of endothelial barrier integrity. These changes were associated with enhanced mitochondrial fission and blocked when Rho-kinase (ROCK) was inhibited. The increases in mitochondrial fission were also associated with the nitration-mediated activation of the small GTPase activator of ROCK, RhoA. Blocking RhoA nitration decreased eNAMPT-mediated mitochondrial fission and endothelial barrier dysfunction. The increase in fission was linked to a RhoA-ROCK mediated increase in Drp1 (dynamin-related protein 1) at serine(S)616. Another TLR4 agonist, lipopolysaccharide (LPS), also increased mitochondrial fission in a Drp1 and RhoA-ROCK-dependent manner. To validate our findings in vivo , we challenged C57BL/6 mice with eNAMPT in the presence and absence of the Drp1 inhibitor, Mdivi-1. Mdivi-1 treatment protected against eNAMPT-induced lung inflammation, edema, and lung injury. These studies demonstrate that mitochondrial fission-dependent disruption of mitochondrial function is essential in TLR4-mediated inflammatory lung injury and identify a key role for RhoA-ROCK signaling. Reducing mitochondrial fission could be a potential therapeutic strategy to improve ARDS outcomes. [Display omitted] • eNAMPT disrupts endothelial barrier integrity and mitochondrial function in pulmonary endothelial cells. • Mitochondrial fission induced by eNAMPT depends on actin cytoskeleton remodeling via Rho-kinase (ROCK). • eNAMPT increases superoxide generation, subsequently activating the small GTPase activator of ROCK (RhoA) via nitration. • Activation of RhoA contributes to the effects of eNAMPT on mitochondrial network dynamics through the activation of Drp1. • Drp1 inhibition is protective against eNAMPT-induced inflammatory lung injury in mice. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Respiratory distress syndrome is a complex inflammatory condition defined by the presence of acute hypoxemia and cellular infiltration with diffuse alveolar injury following a tissue injury, such as acute lung injury. The inflammatory process involved in this pathology is a defense mechanism of the body against infectious agents and/or tissue injuries. However, when the condition is not reversed, it becomes a significant cause of tissue damage, sometimes leading to loss of function of the affected organ. Therefore, it is essential to understand the mechanisms underlying inflammation, as well as the development of new therapeutic agents that reduce inflammatory damage in these cases. Aryl‐cyclohexanone derivatives have previously shown significant anti‐inflammatory activity linked to an immunomodulatory capacity in vitro and may be good candidates for therapies in which inflammation plays a central role.Was evaluated the anti‐inflammatory capacity of a synthesized molecule aryl‐cyclohexanone in the murine model of lipopolysaccharide (LPS)‐induced acute lung injury. The assessment of acute oral toxicity follows the Organization for Economic Co‐operation and Development (OECD) guideline 423.The results demonstrated that the studied molecule protects against LPS‐induced inflammation. We observed a decrease in the migration of total and differential leukocytes to the bronchoalveolar lavage fluid (BALF), in addition to a reduction in exudation, myeloperoxidase (MPO) activity, nitric oxide metabolites, and the secretion of pro‐inflammatory cytokines (alpha tumor necrosis factors [TNF‐α], interleukin‐6 [IL‐6], interferon‐gamma [IFN‐γ], and monocyte chemoattractant protein‐1 [MCP‐1]). Finally, aryl cyclohexanone did not show signs of acute oral toxicity (OECD 423).The results prove our hypothesis that aryl‐cyclohexanone is a promising molecule for developing a new, safe anti‐inflammatory drug. [ABSTRACT FROM AUTHOR]

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and H1N1 viruses are inflammatory lung pathogens that can lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). ALI/ARDS are still life-threatening diseases in critically ill patients with 30–40% mortality in the last decade. Currently, there are no laboratory tests for the early diagnosis or prognosis of ALI/ARDS. Club cell secretory protein (CC16) has been investigated as a potential biomarker of lung epithelial damage in various lung diseases. In this study, we evaluated whether plasma CC16 reflects the severity of COVID-19 and H1N1 infections. The plasma CC16 levels showed no significant differences between H1N1 and COVID-19 groups (p = 0.09). Among all subjects, CC16 levels were significantly higher in non-survivors than in survivors (p = 0.001). Upon the area under the receiver operating characteristic (AUROC) analysis, CC16 had an acceptable value to distinguish survivors and non-survivors (p = 0.002). In the COVID-19 group, plasma CC16 levels moderately correlated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (r = 0.374, p = 0.003) and Sequential Organ Failure Assessment (SOFA) score (r = 0.474, p < 0.001). In the H1N1 group, a positive correlation was observed between the CC16 levels and hospital length of stay (r = 0.311, p = 0.022). Among all the patients, weak correlations between plasma CC16 levels with the SOFA score (r = 0.328, p < 0.001) and hospital length of stay (r = 0.310, p < 0.001) were observed. Thus, circulating CC16 might reflect the severity of COVID-19 and H1N1 infections. [ABSTRACT FROM AUTHOR]

Polymyxin B (PMB) is often considered as the last line of defense for treating carbapenem‐resistant Klebsiella pneumoniae (CRKP). However, its efficacy is hindered by limited penetration across the blood‐air barrier in the lung due to its low lipid solubility. To simultaneously increase PMB in epithelial lining fluid while suppressing the excessive inflammatory response in the lung, a novel nano‐biomimetic system "Siv‐PMB@G4@MM" is designed and fabricated by encapsulating PMB‐ and anti‐inflammatory Sivelestat (Siv)‐loaded G4 PAMAM dendrimers with macrophage membranes (MM). The Siv‐PMB@G4@MM displayed a superior acidic pH‐responsive release property and can target inflamed lung tissues, greatly increasing the concentrations of PMB and Siv at the infection site. Compared with free drugs, Siv‐PMB@G4@MM demonstrated superior synergistic antibacterial and anti‐inflammatory activities. Moreover, due to the ability of MM to sequester lipopolysaccharide (LPS) and some pro‐inflammatory cytokines, Siv‐PMB@G4@MM further enhanced the anti‐inflammatory potential of Siv. In mouse models of LPS‐induced acute lung injury, pulmonary bacterial infection, and sepsis‐induced pneumonia, Siv‐PMB@G4@MM significantly reduced inflammatory responses and/or bacterial burdens, mitigated neutrophil infiltration and pulmonary edema, and decreased neutrophil extracellular trap (NET) secretion. The highly improved biocompatibility and efficiency of the multifunctional Siv‐PMB@G4@MM presents a promising strategy for the clinical treatment of antibiotic‐resistant bacterial pneumonia. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model. Methods: In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically. Results: In vitro, IL-1β, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group. Conclusion: Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis and septic shock are one of the leading causes of death worldwide. Rapid and precise diagnosis and appropriate antibiotic therapy is necessary to reduce mortality and morbidity in patients with sepsis. Though several biomarkers and scoring systems have been evaluated, prognostic markers to quickly and precisely establish the diagnosis or prognosis of patients with sepsis and septic shock are yet to be evaluated. Red cell distribution width (RDW) is measure of erythrocyte size variability and heterogenicity RDW is a newly identified risk marker that has been reported in various studies to be a predictor for morbidity and mortality in sepsis and septic shock. The aim of the study is to determine the values red cell distribution width in patient with sepsis and septic shock. Methodology: This study was a descriptive study including 100 patients who satisfy the Inclusion and exclusion criteria at various medical college tertiary hospital centres, Karnataka. Result: In our study majority were in the age group 61-70yr (38.0%). 27% patients were in age group of 51-60yr, 19% were in age group of 41-50 yr., 13% were in age group of 30-40yr. and 3% were in age group 26-30yr. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the role of Pink1/Parkin-mediated mitochondrial autophagy in exertional heat stroke-induced acute lung injury in rats. METHODS: Sixty SD rats were divided into four groups: normal group (CON group), normal Parkin overexpression group (CON + Parkin group), exertional heat stroke group (EHS group), and exertional heat stroke Parkin overexpression group (EHS + Parkin group). Adeno-associated virus carrying the Parkin gene was intravenously injected into the rats to overexpress Parkin in the lung tissue. An exertional heat stroke rat model was established, and survival curves were plotted. Lung micro-CT was performed, and lung coefficient and pulmonary microvascular permeability were measured. RESULTS: Compared with the EHS group, the survival rate of rats in the EHS + Parkin overexpression group was significantly increased, lung coefficient and pulmonary microvascular permeability were reduced, and pathological changes such as exudation and consolidation were significantly reduced. The levels of inflammatory factors IL-6, IL-1β, TNF- α, and ROS were significantly decreased; the degree of mitochondrial swelling in type II alveolar epithelial cells was reduced, and no vacuolization was observed. Lung tissue apoptosis was reduced, and the colocalization fluorescence of Pink1 and Parkin, as well as LC3 and Tom20, were increased. The expression of Parkin and LC3-II/LC3-I ratio in lung tissue were both increased, while the expression of P62, Pink1, MFN2, and PTEN-L was decreased. CONCLUSION: Impairment of Pink1/Parkin-mediated mitochondrial autophagy function is one of the mechanisms of exertional heat stroke-induced acute lung injury in rats. Activation of the Pink1/Parkin pathway can alleviate acute lung injury caused by exertional heat stroke. [ABSTRACT FROM AUTHOR]

Recent studies have identified exposure to environmental levels of ozone as a risk factor for the development of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) that can develop in humans with sepsis. The aim of this study was to develop a murine model of ALI to mechanistically explore the impact of ozone exposure on ARDS development. Mice were exposed to ozone (0.8 ppm, 3 h) or air control followed 24 h later by intravenous administration of 3 mg/kg lipopolysaccharide (LPS) or PBS. Exposure of mice to ozone + LPS caused alveolar hyperplasia; increased BAL levels of albumin, IgM, phospholipids, and proinflammatory mediators including surfactant protein D and soluble receptor for advanced glycation end products were also detected in BAL, along with markers of oxidative and nitrosative stress. Administration of ozone + LPS resulted in an increase in neutrophils and anti-inflammatory macrophages in the lung, with no effects on proinflammatory macrophages. Conversely, the numbers of resident alveolar macrophages decreased after ozone + LPS; however, expression of Nos2 , Arg1 , Cxcl1 , Cxcl2 , Ccl2 by these cells increased, indicating that they are activated. These findings demonstrate that ozone sensitizes the lung to respond to endotoxin, resulting in ALI, oxidative stress, and exacerbated pulmonary inflammation, and provide support for the epidemiologic association between ozone exposure and ARDS incidence. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) is a critical respiratory condition characterized by a sudden respiratory collapse, accumulation of fluid in lungs leading to reduced blood oxygenation. ALI/ARDS management is mainly supportive, as no specific anti-inflammatory therapy exists for lung injury. Recently, several medicinal plants and natural products have gained attention for their antimicrobial, antioxidant, immunomodulation and anti-inflammatory activities. Cenchrus ciliaris L. (Buffel grass), is native to Africa and Asia where it is traditionally used for several inflammatory disorders, wounds and pain. Cigarette smoke induces inflammation and oxidative stress in respiratory system which can damage lungs and augment respiratory disorders that can progress to ALI/ARDS. We described antioxidant and anti-inflammatory potential of C. ciliaris L. which ameliorates acute lung injury induced by exposure to cigarette smoke. Total phenolic, flavonoid, tannin and saponin contents were quantified in 70 % methanolic extract of C. ciliaris (Cc.Cr). Phytochemical characterization was performed by UHPLC which indicated the presence of furoic acid, longistylin A, scandenin, salicylic acid, piscidic acid, 3-hydroxybenzaldehyde, pheophorbide and chrysoeriol reported for their antioxidant, anti-inflammatory and antimicrobial activities. ALI was induced in mice by exposure to cigarette smoke, followed by the collection of broncho alveolar lavage fluid (BALF) and lung tissues. Total inflammatory cells, differential leukocyte count, total protein contents, nitrite levels, interleukins, total oxidative stress and antioxidant capacity were assessed in BALF. MDA and catalase levels were assessed in lung tissue and histopathology was performed to assess the integrity of lung tissue architecture. Cc.Cr showed good antioxidant activity in CUPRAC and FRAP assays while it effectively scavenged free radicals in DPPH, ABTS and nitric oxide assay. Cc.Cr inhibited cycloxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) with IC 50 values 29.23 ± 9.73 μ g/ml and 24.12 ± 6.0 μ g/ml respectively. In mice, Cc.Cr improved total antioxidant capacity, lung tissue integrity, and hematological parameters while it reduced inflammation, oxidative stress, lung edema and tissue damage. Graphical abstract [Display omitted] • C. ciliaris L. possess good antioxidant and free radical scavenging activity. • It inhibits COX-2 and 5-LOX enzymes. • C. ciliaris L. improves total antioxidant capacity, lung tissue integrity and hematological parameters. • C. ciliaris L. reduced inflammation, oxidative stress, lung edema and tissue damage in acute lung injury. [ABSTRACT FROM AUTHOR]

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) with clinical manifestations of respiratory distress and hypoxemia remains a significant cause of respiratory failure, boasting a persistently high incidence and mortality rate. Given the central role of M1 macrophages in the pathogenesis of acute lung injury (ALI), this study utilized the anti-inflammatory agent curcumin as a model drug. l -arginine (L-Arg) was employed as a targeting ligand, and chitosan was initially modified with l -arginine. Subsequently, it was utilized as a surface modifier to prepare inhalable nano-crystals loaded with curcumin (Arg-CS-Cur), aiming for specific targeting of pulmonary M1 macrophages. Compared with unmodified chitosan-curcumin nanocrystals (CS-Cur), Arg-CS-Cur exhibited higher uptake in vitro by M1 macrophages, as evidenced by flow cytometry showing the highest fluorescence intensity in the Arg-CS-Cur group (P < 0.01). In vivo accumulation was greater in inflamed lung tissues, as indicated by small animal imaging demonstrating higher lung fluorescence intensity in the DiR-Arg-CS-Cur group compared to the DiR-CS-Cur group in the rat ALI model (P < 0.05), peaking at 12 h. Moreover, Arg-CS-Cur demonstrated enhanced therapeutic effects in both LPS-induced RAW264.7 cells and ALI rat models. Specifically, treatment with Arg-CS-Cur significantly suppressed NO release and levels of TNF-α and IL-6 in RAW264.7 cells (p < 0.01), while in ALI rat models, expression levels of TNF-α and IL-6 in lung tissues were significantly lower than those in the model group (P < 0.01). Furthermore, lung tissue damage was significantly reduced, with histological scores significantly lower than those in the CS-Cur group (P < 0.01). In conclusion, these findings underscore the targeting potential of l -arginine-modified nanocrystals, which effectively enhance curcumin concentration in inflammatory environments by selectively targeting M1 macrophages. This study thus introduces novel perspectives and theoretical support for the development of targeted therapeutic interventions for acute inflammatory lung diseases, including ALI/ARDS. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a life-threatening clinical disorder with high mortality rate. Ferroptosis is a new type of programmed cell death with lipid peroxidation and iron ion overloading as the main characteristics. Endoplasmic reticulum (ER) stress and ferroptosis play pivotal roles in the pathogenesis of ALI. The study aimed to investigate the underlying relationship between ER stress and ferroptosis in ALI. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated LPS-induced inflammation, and decreased IL-1β, IL-6, and TNF-α levels in BALF and lungs. The increased MDA and decreased GSH induced by LPS were partially reversed by 4-PBA, which also inhibited the expressions of ferroptosis-related protein ACSL4, COX-2, and FTH1. TEM further confirmed the ferroptosis within airway epithelia cells was ameliorated by 4-PBA. Moreover, 4-PBA reduced the production of ROS and lipid ROS in LPS-exposed BEAS-2B cells in a concentration-dependent way. Meanwhile, 4-PBA mitigated LPS-induced cell apoptosis in vivo and in vitro. Mechanistically, the MAPK signaling pathway activated by LPS was downregulated by 4-PBA. Collectively, these findings suggested that 4-PBA protected against ALI by inhibiting inflammation and ferroptosis through downregulating ER stress, thus providing a potential intervention for ALI and revealing the possible interaction between ER stress and ferroptosis in ALI. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper‐inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS). Objectives: Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI. Methods: The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll‐ and nucleotide‐binding oligomerization domain (NOD)‐like receptors, alveolar damage, pro‐inflammatory cytokines, and epithelial/endothelial damage alone or in combination. Results: This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs). Conclusion: However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure‐based drug design, in‐silico approaches, and drug repurposing. [ABSTRACT FROM AUTHOR]

Golden buckwheat, also called Fagopyrum dibotrys (D. Don) H. Hara, is a plant of the genus Buckwheat in the buckwheat family. The aim of this study was to screen the bioactive ingredients of golden buckwheat extract and investigate the protective effect on acute lung injury (ALI). The ethyl acetate extract (EAE) was identified as the active fraction in LPS‐induced RAW264.7 cells, with gallic acid, proanthocyanidin B2, and epicatechin at 0.0563%, 0.3707%, and 0.3868%, respectively. At the same time, 20 compounds (mainly flavonoids and organic acids) were identified by UPLC‐Q‐Exactive Orbitrap‐HRMS in EAE. Furthermore, the EAE reduced lung histopathology scores in mice with ALI, decreased the dry‐to‐wet weight ratio of lung tissue, and significantly inhibited the concentrations of IL‐1β, TNFα, and IL‐6 in bronchoalveolar lavage fluid (BALF). It also reduced the number of leukocytes, decreased the activity of MPO in lung tissue, and inhibited the levels of TLR4/NLRP3 pathway mRNA and protein in lung tissue. Our study indicated that golden buckwheat as a source of functional food prevents or treats associated lung diseases by modulating the activation of the TLR4/NLRP3 signaling pathway. [ABSTRACT FROM AUTHOR]

Background and main body: Although interactions between the nervous and immune systems have been recognized decades ago, it has become increasingly appreciated that neuroimmune crosstalk is among the driving factors of multiple pulmonary inflammatory diseases including acute lung injury (ALI). Here, we review the current understanding of nerve innervations towards the lung and summarize how the neural regulation of immunity and inflammation participates in the onset and progression of several lung diseases, especially ALI. We then present advancements in the development of potential drugs for ALI targeting neuroimmune interactions, including cholinergic anti‐inflammatory pathway, sympathetic‐immune pathway, purinergic signalling, neuropeptides and renin‐angiotensin system at different stages from preclinical investigation to clinical trials, including the traditional Chinese medicine. Conclusion: This review highlights the importance of considering the therapeutic strategy of inflammatory diseases within a conceptual framework that integrates classical inflammatory cascade and neuroimmune circuits, so as to deepen the understanding of immune modulation and develop more sophisticated approaches to treat lung diseases represented by ALI. Key points: The lungs present abundant nerve innervations.Neuroimmune interactions exert a modulatory effect in the onset and progression of lung inflammatory diseases, especially acute lung injury.The advancements of potential drugs for ALI targeting neuroimmune crosstalk at different stages from preclinical investigation to clinical trials are elaborated.Point out the direction for the development of neuroimmune pharmacology in the future. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate‐limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)‐induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin‐10 (IL‐10). Methods: After nasal inhalation rIL‐10 and/or LPS, wild type (WT), IL‐10‐/‐, Cre‐CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow‐derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL‐10 and/or LPS. The qRT‐PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. Results: In in vivo experiments, we found that mice lacking CPT1A or IL‐10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL‐10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL‐10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL‐10‐/‐ BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL‐10 into macrophages showed reverse effect. CPT1A and IL‐10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A‐IL‐10 axis is also involved in the process of maintaining mitochondrial homeostasis. Conclusions: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL‐10/IL‐10 receptor expression. [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]

Neutrophils are the first leukocytes to be recruited to sites of inflammation in response to chemotactic factors released by activated macrophages and pulmonary epithelial and endothelial cells in bacterial pneumonia, a common cause of acute respiratory distress syndrome (ARDS). Although neutrophilic inflammation facilitates the elimination of pathogens, neutrophils also may cause bystander tissue injury. Even though the presence of neutrophils in alveolar spaces is a key feature of acute lung injury and ARDS especially from pneumonia, their contribution to the pathogenesis of lung injury is uncertain. The goal of this study was to elucidate the role of neutrophils in a clinically relevant model of bacterial pneumonia. We investigated the effect of reducing neutrophils in a mouse model of pneumococcal pneumonia treated with antibiotics. Neutrophils were reduced with anti-lymphocyte antigen 6 complex locus G6D (Ly6G) monoclonal antibody 24 h before and immediately preceding infection. Mice were inoculated intranasally with Streptococcus pneumoniae and received ceftriaxone 12 h after bacterial inoculation. Neutrophil reduction in mice treated with ceftriaxone attenuated hypoxemia, alveolar permeability, epithelial injury, pulmonary edema, and inflammatory biomarker release induced by bacterial pneumonia, even though bacterial loads in the distal air spaces of the lung were modestly increased as compared with antibiotic treatment alone. Thus, when appropriate antibiotics are administered, lung injury in the early phase of bacterial pneumonia is mediated in part by neutrophils. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense. NEW & NOTEWORTHY: Neutrophil accumulation is a key feature of ARDS, but their contribution to the pathogenesis is still uncertain. We investigated the effect of reducing neutrophils in a clinically relevant mouse model of pneumococcal pneumonia treated with antibiotics. When appropriate antibiotics were administered, neutrophil reduction with Ly6G antibody markedly attenuated lung injury and improved oxygenation. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a high-mortality disease caused by multiple disorders such as COVID-19, influenza, and sepsis. Current therapies mainly rely on the inhalation of nitric oxide or injection of pharmaceutical drugs (e.g., glucocorticoids); however, their toxicity, side effects, or administration routes limit their clinical application. In this study, pachypodol (Pac), a hydrophobic flavonol with anti-inflammatory effects, was extracted from Pogostemon cablin Benth and intercalated in liposomes (Pac@liposome, Pac-lipo) to improve its solubility, biodistribution, and bioavailability, aiming at enhanced ALI/ARDS therapy. Nanosized Pac-lipo was confirmed to have stable physical properties, good biodistribution, and reliable biocompatibility. In vitro tests proved that Pac-lipo has anti-inflammatory property and protective effects on endothelial and epithelial barriers in lipopolysaccharide (LPS)-induced macrophages and endothelial cells, respectively. Further, the roles of Pac-lipo were validated on treating LPS-induced ALI in mice. Pac-lipo showed better effects than did Pac alone on relieving ALI phenotypes: It significantly attenuated lung index, improved pulmonary functions, inhibited cytokine expression such as TNF-α, IL-6, IL-1β, and iNOS in lung tissues, alleviated lung injury shown by HE staining, reduced protein content and total cell number in bronchoalveolar lavage fluid, and repaired lung epithelial and vascular endothelial barriers. As regards the underlying mechanisms, RNA sequencing results showed that the effects of the drugs were associated with numerous immune- and inflammation-related signaling pathways. Molecular docking and western blotting demonstrated that Pac-lipo inhibited the activation of the TLR4-MyD88-NF-κB/MAPK signaling pathway. Taken together, for the first time, our new drug (Pac-lipo) ameliorates ALI via inhibition of TLR4-MyD88-NF-κB/MAPK pathway-mediated inflammation and disruption of lung barrier. These findings may provide a promising strategy for ALI treatment in the clinic. [Display omitted] [ABSTRACT FROM AUTHOR]

Sepsis‐induced acute lung injury (ALI) is characterized by inflammatory damage to pulmonary endothelial and epithelial cells. The aim of this study is to probe the significance and mechanism of tripartite motif‐containing protein 21 (TRIM21) in sepsis‐induced ALI. The sepsis‐induced ALI mouse model was established by cecum ligation and puncture. The mice were infected with lentivirus and treated with proteasome inhibitor MG132. The lung respiratory damage, levels of interleukin‐6 (IL‐6), tumour necrosis factor α (TNF‐α), IL‐10 and pathological changes were observed. The expression levels of TRIM21, interferon regulatory factors 1 (IRF1) and triggering receptor expressed on myeloid cells 2 (TREM2) were measured and their interactions were analysed. The ubiquitination level of IRF1 was detected. TRIM21 and TREM2 were downregulated and IRF1 was upregulated in sepsis‐induced ALI mice. TRIM21 overexpression eased inflammation and lung injury. TRIM21 promoted IRF1 degradation via ubiquitination modification. IRF1 bonded to the TREM2 promoter to inhibit its transcription. Overexpression of IRF1 or silencing TREM2 reversed the improvement of TRIM21 overexpression on lung injury in mice. In conclusion, TRIM21 reduced IRF1 expression by ubiquitination to improve TREM2 expression and ameliorate sepsis‐induced ALI. [ABSTRACT FROM AUTHOR]

Sepsis has a high mortality rate and leads to multi-organ failure, including lung injury. Inactive rhomboid protease family protein (iRhom2) has been identified as accountable for the release of TNF-α, a crucial mediator in the development of sepsis. This study aimed to evaluate the role of iRhom2 in sepsis and sepsis-induced acute lung injury (ALI). TNF-α and IL-6 secretion in vitro by peritoneal macrophages from wild-type (WT) and iRhom2 knoukout (KO) mice was assessed by enzyme-linked immunosorbent assay. Cecal ligation and puncture (CLP)-induced murine sepsis model was used for in vivo experiments. To evaluate the role of iRhom2 deficiency on survival during sepsis, both WT and iRhom2 KO mice were monitored for 8 consecutive days following the CLP. For histologic and biochemical examination, the mice were killed 18 h after CLP. iRhom2 deficiency improved the survival of mice after CLP. iRhom2 deficiency decreased CD68+ macrophage infiltration in lung tissues. Multiplex immunohistochemistry revealed that the proportion of Ki-67+ CD68+ macrophages was significantly lower in iRhom2 KO mice than that in WT mice after CLP. Moreover, CLP-induced release of TNF-α and IL-6 in the serum were significantly inhibited by iRhom2 deficiency. iRhom2 deficiency reduced NF-kB p65 and IκBα phosphorylation after CLP. iRhom2 deficiency reduces sepsis-related mortality associated with attenuated macrophage infiltration and proliferation in early lung injury. iRhom2 may play a pivotal role in the pathogenesis of sepsis and early stage of sepsis-induced ALI. Thus, iRhom2 may be a potential therapeutic target for the management of sepsis and sepsis-induced ALI. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is characterized by an unregulated inflammatory reaction, often leading to severe morbidity and ultimately death. Excessive inflammation caused by M1 macrophage polarization and pyroptosis has been revealed to have a critical role in ALI. Recent study suggests that glycolytic reprogramming is important in the regulation of macrophage polarization and pyroptosis. However, the particular processes underlying ALI have yet to be identified. In this study, we established a Lipopolysaccharide(LPS)-induced ALI model and demonstrated that blocking glycolysis by using 2-Deoxy-D-glucose(2-DG) significantly downregulated the expression of M1 macrophage markers and pyroptosis-related genes, which was consistent with the in vitro results. Furthermore, our research has revealed that Phosphoglycerate Kinase 1(PGK1), an essential enzyme in the glycolysis pathway, interacts with NOD-, LRR- and pyrin domain-containing protein 3(NLRP3). We discovered that LPS stimulation improves the combination of PGK1 and NLRP3 both in vivo and in vitro. Interestingly, the absence of PGK1 reduces the phosphorylation level of NLRP3. Based on in vitro studies with mice bone marrow-derived macrophages (BMDMs), we further confirmed that siPGK1 plays a protective role by inhibiting macrophage pyroptosis and M1 macrophage polarization. The PGK1 inhibitor NG52 suppresses the occurrence of excessive inflammation in ALI. In general, it is plausible to consider a therapeutic strategy that focuses on modulating the relationship between PGK1 and NLRP3 as a means to mitigate the activation of inflammatory macrophages in ALI. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of acute lung injury (ALI) involves a severe inflammatory response, leading to significant morbidity and mortality. N6-methylation of adenosine (m6A), an abundant mRNA nucleotide modification, plays a crucial role in regulating mRNA metabolism and function. However, the precise impact of m6A modifications on the progression of ALI remains elusive. Methods: ALI models were induced by either intraperitoneal injection of lipopolysaccharide (LPS) into C57BL/6 mice or the LPS-treated alveolar type II epithelial cells (AECII) in vitro. The viability and proliferation of AECII were assessed using CCK-8 and EdU assays. The whole-body plethysmography was used to record the general respiratory functions. M6A RNA methylation level of AECII after LPS insults was detected, and then the "writer" of m6A modifications was screened. Afterwards, we successfully identified the targets that underwent m6A methylation mediated by METTL3, a methyltransferase-like enzyme. Last, we evaluated the regulatory role of METTL3-medited m6A methylation at phosphatase and tensin homolog (Pten) in ALI, by assessing the proliferation, viability and inflammation of AECII. Results: LPS induced marked damages in respiratory functions and cellular injuries of AECII. The m6A modification level in mRNA and the expression of METTL3, an m6A methyltransferase, exhibited a notable rise in both lung tissues of ALI mice and cultured AECII cells subjected to LPS treatment. METTL3 knockdown or inhibition improved the viability and proliferation of LPS-treated AECII, and also reduced the m6A modification level. In addition, the stability and translation of Pten mRNA were enhanced by METTL3-mediated m6A modification, and over-expression of PTEN reversed the protective effect of METTL3 knockdown in the LPS-treated AECII. Conclusions: The progression of ALI can be attributed to the elevated levels of METTL3 in AECII, as it promotes the stability and translation of Pten mRNA through m6A modification. This suggests that targeting METTL3 could offer a novel approach for treating ALI. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of acute lung injury (ALI) involves a severe inflammatory response, leading to significant morbidity and mortality. N6-methylation of adenosine (m6A), an abundant mRNA nucleotide modification, plays a crucial role in regulating mRNA metabolism and function. However, the precise impact of m6A modifications on the progression of ALI remains elusive. Methods: ALI models were induced by either intraperitoneal injection of lipopolysaccharide (LPS) into C57BL/6 mice or the LPS-treated alveolar type II epithelial cells (AECII) in vitro. The viability and proliferation of AECII were assessed using CCK-8 and EdU assays. The whole-body plethysmography was used to record the general respiratory functions. M6A RNA methylation level of AECII after LPS insults was detected, and then the "writer" of m6A modifications was screened. Afterwards, we successfully identified the targets that underwent m6A methylation mediated by METTL3, a methyltransferase-like enzyme. Last, we evaluated the regulatory role of METTL3-medited m6A methylation at phosphatase and tensin homolog (Pten) in ALI, by assessing the proliferation, viability and inflammation of AECII. Results: LPS induced marked damages in respiratory functions and cellular injuries of AECII. The m6A modification level in mRNA and the expression of METTL3, an m6A methyltransferase, exhibited a notable rise in both lung tissues of ALI mice and cultured AECII cells subjected to LPS treatment. METTL3 knockdown or inhibition improved the viability and proliferation of LPS-treated AECII, and also reduced the m6A modification level. In addition, the stability and translation of Pten mRNA were enhanced by METTL3-mediated m6A modification, and over-expression of PTEN reversed the protective effect of METTL3 knockdown in the LPS-treated AECII. Conclusions: The progression of ALI can be attributed to the elevated levels of METTL3 in AECII, as it promotes the stability and translation of Pten mRNA through m6A modification. This suggests that targeting METTL3 could offer a novel approach for treating ALI. [ABSTRACT FROM AUTHOR]

AIM: To investigate the protective effect of total flavonoids from Patrina villosa Juss (PJF) on the lung in an experimental rat model of acute lung injury (ALI), and to elucidate the potential mechanism. METHODS: The ALI rat model was established by instilling 5 mg/kg of lipopolysaccharide (LPS) into the airway. Sixty male SD rats were randomly divided into 4 groups: control, LPS, LPS+low-dose PJF (receiving 100 mg/kg PJF one hour before ALI modeling) and LPS+high-dose PJF (receiving 300 mg/kg PJF one hour before ALI modeling). Each group consisted of 15 animals. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected from all groups 24 h after modeling. For assessment of lung tissue morphology, HE staining was performed. The wet/dry weight ratio of the lung tissue was determined using the wet/dry weighing method. Evans blue staining was conducted to assess epithelial barrier permeability in lung tissues. ELISA was used to detect the levels of inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 in the BALF, as well as oxidative stress markers including superoxide dismutase (SOD), myeloperoxi-dase (MPO) and glutathione peroxidase (GSH-Px) activity, and malondialdehyde (MDA) content in the lung tissue. The expression levels of C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78) and X-box binding protein 1 (XBP1) in the lung tissue were analyzed by Western blotting. RESULTS: Compared with control group, the rats in LPS group exhibited a blurred alveolar structure with a significant infiltration of inflammatory cells. The ALI score and the wet/dry weight ratio of the lung tissue were increased (P<0. 05). Concurrently, the levels of IL-6, IL-1β and TNF-α in the BALF, along with MDA content and MPO activity in the lung tissue, were elevated (P<0. 05). Additionally, the protein levels of CHOP, GRP78 and XBP1 were up-regulated in the lung tissue (P<0. 05), while the SOD and GSH-Px activity was significantly decreased (P<0. 05). Compared with LPS group, PJF intervention exerted beneficial effects on the lung tissue morphology with reduced ALI score and lower lung wet/dry weight ratio (P<0. 05). Moreover, the levels of IL-6, IL-1β and TNF-α in BALF, as well as MDA content, MPO activity and the protein levels of CHOP, GRP78 and XBP1 in the lung tissue were all significantly decreased (P<0. 05), while the SOD and GSH-Px activity was significantly increased (P<0. 05). The efficacy in high-dose group exceeded that in low-dose group. CONCLUSION: The PJF have protective effect on the lungs of rats with ALI, and its mechanism may be related to the inhibition of inflammation, oxidative stress and endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Background: Endothelial barrier dysfunction is critical for the pathogenesis of sepsis-induced acute lung injury (ALI). Lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cells (HPMECs) are widely used as the cell model of sepsis-associated ALI for exploration of endothelial barrier dysfunction. Dickkopf (DKK) family proteins were reported to mediate endothelial functions in various diseases. The present study explored the effect of Dickkopf-3 (DKK3) on endothelial barrier permeability, angiogenesis, and tight junctions in LPS-stimulated HPMECs. Methods: RT-qPCR was required for detecting DKK3 and miR-98-3p expression. The angiogenesis of HPMECs was evaluated by tube formation assays. Monolayer permeability of HPMECs was examined by Transwell rhodamine assays. The protein expression of DKK3 and tight junctions in HPMECs was measured via western blotting. Luciferase reporter assay was used to verify the interaction between miR-98-3p and DKK3. Results: LPS treatment inhibited angiogenetic ability while increasing the permeability of HPMECs. DKK3 expression was upregulated while miR-98-3p level was reduced in LPS-treated HPMECs. DKK3 knock-down alleviated HPMEC injury triggered by LPS stimulation. MiR-98-3p targeted DKK3 in HPMECs. Overexpression of miR-98-3p protects HPMECs from the LPS-induced endothelial barrier dysfunction, and the protective effect was reversed by DKK3 overexpression. Conclusions: MiR-98-3p ameliorates LPS-evoked pulmonary microvascular endothelial barrier dysfunction in sepsis-associated ALI by targeting DKK3. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of γ -aminobutyric acid (GABA) signaling pathway on endoplasmic reticulum (ER) stress and mitochondrial autophagy in septic rats with acute lung injury (ALI). Methods SD rats were randomly grouped into the control (CON) group, the model group, the GABA signaling pathway activator Baclofen group (the Baclofen group), the GABA signaling pathway inhibitor dicentrine group (the BIC group), with 6 rats in each group. The Baclofen group received intraperitoneal injection of 5 mg/kg Baclofen, and the BIC group received intraperitoneal injection of 1 mg/kg BIC, once a day, for two consecutive weeks. The CON group and the model group were injected with an equal amount of physiological saline via intraperitoneal injection. Enzyme linked immunosorbent assay was applied to detect serum levels of superoxide dismutase (SOD) and malondialdehyde (MDA) and levels of cytochrome C (Cyt.C) and Nicotinamide adenine dinucleotide phosphate (NADPH) in bronchoalveolar lavage fluid (BALF). Transmission electron microscopy (TEM) was applied to observe the ultrastructure of lung tissue cells. HE staining was applied to observe the pathological morphology of lung tissue. TUNEL staining was applied to observe the apoptosis of lung tissue. Western blot assay was applied to detect expression levels of GABAAR, GRP78 and CHOP proteins in lung tissue. Results Compared with the model group, the lung swelling, congestion and inflammatory cell infiltration were improved in the Baclofen group, and the lung injury score, MDA content, apoptosis index, Cyt.C and NADPH levels, GRP78, and CHOP protein levels were reduced (P＜0.05). The number of autophagic vacuoles in phagocytic mitochondria, SOD content and GABAAR protein level were increased (P＜ 0.05), however, the trend of above indicators in the BIC group was opposite to that in the Baclofen group. Conclusion Upregulation of GABA signaling pathway may have an improvement effect on ALI in sepsis rats. [ABSTRACT FROM AUTHOR]

Sepsis‐induced acute lung injury (ALI) is a severe complication of sepsis. Karanjin, a natural flavonoid compound, has been proved to have anti‐inflammatory function, but its role in sepsis‐stimulated ALI is uncertain. Herein, the effect of karanjin on sepsis‐stimulated ALI was investigated. We built a mouse model of lipopolysaccharide (LPS)‐stimulated ALI. The histopathological morphology of lung tissues was scrutinized by hematoxylin–eosin (H&E) staining. The lung injury score and lung wet/dry weight ratio were detected. The myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were scrutinized by commercial kits. Murine alveolar lung epithelial (MLE‐12) cells were treated with LPS to mimic a cellular model of ALI. The cell viability was scrutinized by the CCK‐8 assay. The contents of proinflammatory cytokines were scrutinized by qRT‐PCR and ELISA. The TLR4 and MyD88 contents were scrutinized by qRT‐PCR and western blotting. Results showed that karanjin alleviated LPS‐stimulated ALI in mice by inhibiting lung tissue lesions, edema, and oxidative stress. Moreover, karanjin inhibited LPS‐stimulated inflammation and TLR4 pathway activation in mice. However, treatment with GSK1795091, an agonist of TLR4, attenuated the effects of karanjin on LPS‐induced ALI. Furthermore, karanjin repressed LPS‐stimulated inflammatory response and TLR4 pathway activation in MLE‐12 cells. Overexpression of TLR4 attenuated karanjin effects on LPS‐stimulated inflammatory responses in MLE‐12 cells. In conclusion, karanjin repressed sepsis‐stimulated ALI in mice by suppressing the TLR4 pathway. [ABSTRACT FROM AUTHOR]

Background and aim: Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux. Methods and results: We conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane. Conclusion: These findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis. [ABSTRACT FROM AUTHOR]