Lung Injury Research Articles

Single-cell analysis of the decidua unveils the mechanism of anti-inflammatory exosomes for chorioamnionitis in nonhuman primates.

The effectiveness of exosomes engineered to carry a dominantly active variant of inhibitor α of nuclear factor κB (NF-κB) (IκBα), super-repressor IκB (srIκB), that inhibits the expression of NF-κB in various animal models of inflammatory diseases has been demonstrated. In this study, we used a lipopolysaccharide (LPS)-induced chorioamnionitis model in pregnant nonhuman primates to explore the therapeutic potential and mode of action of srIκB-loaded exosomes (Exo-srIκBs). Intraamniotic injection of LPS induced infiltration of BCL2A1-positive neutrophils and CD68-positive macrophages in the extraplacental membranes, causing fetal lung injury. Conversely, administration of Exo-srIκB via intraamniotic and intravenous routes (6.9×1010 and 4×1011 particle numbers, respectively) ameliorated these effects. Single-cell RNA sequencing of the decidua and bulk RNA sequencing of the choriodecidua highlighted that Exo-srIκB treatment mitigated LPS-induced inflammatory pathways, particularly in macrophages, leading to a cascade effect on neutrophils through NF-κB signaling inhibition. These findings underscore the potential of Exo-srIκB as a therapeutic strategy for chorioamnionitis.

ARF3 knockdown inhibits influenza a virus and virus-induced pneumonia.

Pneumonia, characterized by infection-induced inflammation of the lungs, poses a significant health burden, particularly among children. ADP ribosylation factor 3 (ARF3) is a key regulatory protein implicated in various pathological processes; however, its role in pneumonia caused by influenza A virus (IAV) remains inadequately understood. In this study, we demonstrated that ARF3 expression was upregulated in a young mouse model of IAV-induced pneumonia. Knockdown of ARF3 effectively mitigated lung injury in this model. Furthermore, suppression of ARF3 expression alleviated pulmonary inflammation by reducing the levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β. In vitro experiments further revealed that ARF3 downregulation inhibited replication of the H3N2 IAV strain. Notably, ARF3 knockdown also attenuated NLRP3 inflammasome activation, a key mediator of inflammatory responses. Collectively, these findings provide the first evidence that ARF3 knockdown suppresses both IAV replication and virus-induced pneumonia by modulating inflammasome activation, suggesting that ARF3 may serve as a potential therapeutic target for pneumonia intervention.

KAT3B Protects Against Septic Lung Injury by Regulating TSLP Succinylation and Macrophage Polarization.

As a serious complication of sepsis, septic lung injury has a high rate of morbidity and mortality. However, the mechanism of septic lung injury remain unclear.The present study aims to explore the role of succinylation and KAT3B in the polarization of macrophages and the progression of septic lung injury.The cecal ligation and puncture (CLP) was used to establish the septic lung injury model. HE staining was performed to evaluate the lung injury. Raw264.7 cells were treated with lipopolysaccharide (LPS) to establish the cell model of septic lung injury. Macrophage polarization was evaluated by detecting M1 and M2 markers using quantitative real-time polymerase chain reaction and immunofluorescence. CO-IP was used to investigate the interaction between proteins.The experimental results indicated that KAT3B and the total succinylation was down-regulated in septic lung injury. LPS promoted M1 polarization and inhibited M2 polarization of Raw264.7 cells. KAT3B suppressed M1 polarization and promoted M2 polarization. Mechanistically, KAT3B desuccinylates TSLP at K239 and K292 site and promotes its stability. TSLP silencing reversed the effects of KAT3B. In vivo, KAT3B significantly reduced the lung injury and inflammation response of mice after CLP treatment.The present research unveiled the KAT3B acts as a protector against sepsis induced injury by mediating the succinylation of TLSP.

Single-cell transcriptomic analysis reveals therapeutic mechanisms of adipose-derived stem cell exosomes in sepsis-induced lung injury.

Sepsis-induced acute lung injury (ALI) remains a leading cause of mortality in critically ill patients, with limited effective treatments beyond supportive care. This study investigates the therapeutic efficacy and underlying mechanisms of adipose-derived stem cell (ADSC) exosomes on sepsis-induced lung injury and characterize underlying cellular and molecular mechanisms. We employed a cecal ligation and puncture (CLP) mouse model of sepsis and using male C57BL/6J mice (Mus musculus, 8-10weeks old) and administered ADSC-derived exosomes intravenously. Animals were randomly assigned to Sham, CLP, or CLP+ADSC-exosome groups. Survival rates (n=12 for each group) and lung histopathology (n=5 for each group) were assessed. Single-cell RNA sequencing was performed on lung tissues to analyze cell type-specific transcriptomic changes and intercellular communication networks (n=2 for each group). ADSC exosome treatment significantly improved survival rates and reduced lung pathology in CLP mice. Treatment altered lung cellular composition, increasing neutrophils, NKT cells, and monocytes while decreasing B and T cells. Gene expression analysis revealed downregulation of pro-inflammatory markers (TNF, IL-10, CCL3, CCL4) and upregulation of tissue repair pathways. In neutrophils, exosomes reduced expression of respiratory burst genes while enhancing tissue repair mechanisms. In monocytes, treatment suppressed inflammatory cytokine production while promoting anti-inflammatory phenotypes. Exosome treatment is associated with transcriptomic changes suggestive of restored intercellular communication networks disrupted by sepsis, with increased signaling via CSF3, ANGPT, SPP1, and CCL pathways. ADSC-derived exosomes effectively treat sepsis-induced lung injury by rebalancing the cellular environment and restoring homeostasis through modulation of immune cell function and intercellular communication, offering potential as a cell-free novel therapeutic approach for sepsis-related pulmonary complications.

The role and mechanism of lung microbiota in coal mine dust-induced NLRP3 inflammasome upregulate and lung injury

The exact molecular mechanisms of coal workers’ pneumoconiosis (CWP) are still unknown. The purpose of this study is to investigate how the lung microbiota may contribute to the development of CWP. The rats were divided into five groups, including the control group, CWP group, silicosis group, CWP + antibiotic group, and CWP + MCC950 group. An animal model of CWP and silicosis was established using a non-exposed tracheal instillation method. The CWP + antibiotic group was treated with drinking and nasal drip broad-spectrum antibiotics in CWP rats, while the CWP + MCC950 group received intraperitoneal injections of NLRP3 inhibitors MCC950 in CWP rats. 16S rRNA sequencing was used to detect the lung microbiota in rats. Real-time fluorescence quantitative PCR was performed to detect the expression of NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1, IL-1β, collagen I, and fibronectin. The lung microbiota of exposed to coal dust exhibits an increase in Firmicutes, Staphylococcus, and Streptococcus, and decreases in Bacteroidota, Rothia, Achromobacter, and Lactobacillus, and an increase in mRNA levels of fibrotic and inflammatory markers. Antibiotic intervention and MCC950 had consistent impacts on the predominant microbiota in the lungs and the changes are essentially in opposition to the trends found in the CWP and control groups, whereas mRNA levels of fibrotic and inflammatory markers reduced. The richness of some prominent bacterial communities changed as a result of coal dust exposure, which could be a contributing factor to the inflammation and fibrosis caused by coal dust. Lung microbiota may serve as a key pathogenic mechanism in CWP.

Acetic Acid Inhalation-Induced Lung Injury: A Common Chemical with Underestimated Risks.

Acetic acid is widely used; however, its inhalation can cause significant respiratory harm. This paper examines its toxicological mechanisms, overlooked health risks, and the need for targeted safety measures to prevent lung injury in both domestic and occupational places.

Is Altered Surfactant Protein Gene Expression in Peripheral Blood Associated with COVID-19 Disease Severity?

Background/Objectives: Severe COVID-19 pneumonia damages alveolar type II cells and disrupts surfactant homeostasis, contributing to acute respiratory distress syndrome (ARDS). Surfactant proteins (SP-A, SP-B, SP-C, SP-D) are critical for reducing alveolar surface tension and for innate immune defense. We aimed to evaluate whether surfactant protein gene expression varies with the severity of COVID-19. Methods: Peripheral blood was collected from 122 adults with confirmed COVID-19, categorized as asymptomatic (no symptoms), mild (requiring hospitalization), or severe (requiring ICU admission). We quantified mRNA expression of surfactant protein genes (SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD) in blood cells using RT-qPCR. Relative expression was normalized to GAPDH and compared among the groups using the 2−ΔΔCt method. Outliers (Ct values > 3 SD from the mean) were excluded before analysis. Results: Distinct surfactant gene expression patterns were markedly associated with disease severity. Transcripts of SFTPB and SFTPC decreased with increasing severity of the disease. Notably, SFTPC expression was ~49-fold higher in mild cases compared to asymptomatic COVID-19-positive patients (p < 0.0001), but then decreased by ~54-fold in severe cases relative to mild (p < 0.0001), returning to near-baseline levels. In contrast, SFTPA2 and SFTPD were dramatically upregulated in severe cases. SFTPA2 was ~50-fold higher in severe versus mild cases (p < 0.0001), and SFTPD was ~4346-fold higher in severe versus asymptomatic cases (p < 0.0001; ~9.6-fold higher than in mild). SFTPA1 showed only a modest ~1.4-fold decrease in severe cases (vs. mild). All noted differences remained statistically significant after outlier exclusion. Conclusions: COVID-19 severity is correlated with profound changes in surfactant gene expression in blood. Critically ill patients exhibit loss of key surfactant components (SP-B and SP-C transcripts) alongside an excessive SP-D response. These preliminary findings suggest an imbalance that may contribute to lung injury in severe disease. However, further validation is needed to establish surfactant proteins, such as SP-D, as biomarkers of COVID-19 severity.

MSCs regulate oxidative stress through the Nrf2 pathway to treat chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) has become a great public health concern. While existing treatments can provide relief from COPD, they do not cure the disease. Stem cell transplantation is an emerging treatment modality that may play an important role in COPD treatment.MethodsA COPD model was constructed by exposing mice to tobacco smoke and administering bacterial lipopolysaccharide via intranasal drops. The progression of COPD was monitored after the transplantation of MSCs, and oxidative stress-related pathways were evaluated to explore the relationship among COPD, oxidative stress and stem cell transplantation. HE staining and Masson’s trichrome staining were used to detect pulmonary lesions and the degree of pulmonary fibrosis. The levels of oxidative stress-related molecules were evaluated via qRT‒PCR and ELISA. Nrf2 pathway molecule expression was detected by immunofluorescence.ResultsCompared with the control group, we successfully established a tobacco smoke-induced COPD model with an increased lung macrophage number, inflammatory cell infiltration, enlarged alveoli, and pulmonary fibrosis. After MSC transplantation, the oxidative stress level was reduced, and the lung condition improved, 4-HNE in COPD mice decreased by 90pg/mg prot, IL-6 decreased by 15.55pg/ml, ROS decreased by 1.9 × 107, PCT in the blood decreased by 0.51 µg/L, EOS decreased by 29.02%, and WBC decreased by 3.41^9/L. CRP decreased by 15.8 mg/ml. In addition, our data suggest that MSCs may mitigate lung injury from COPD by reducing oxidative stress through the regulation of the Nrf2 pathway.ConclusionThis study confirmed the therapeutic effect of transplanted MSCs on tobacco- and lipopolysaccharide-induced COPD and revealed that MSCs ameliorate COPD by regulating oxidative stress-related pathways.Clinical trial numberNot applicable.

Association Between Driving Pressure and Subsequent Development of Acute Kidney Injury in Acute Respiratory Distress Syndrome.

Although preclinical evidence indicates that injurious mechanical ventilation may lead to acute kidney injury (AKI), relevant clinical evidence is limited. We aimed to investigate the association of driving pressure (a marker of injurious mechanical ventilation) with subsequent development of AKI in patients with acute respiratory distress syndrome (ARDS). Secondary analysis of individual patient-level data from seven ARDS Network and Prevention and Early Treatment of Acute Lung Injury (PETAL) Network randomized controlled clinical trials. Adult ICUs participating in the ARDS Network and PETAL Network trials. After exclusion of patients with early AKI (i.e., those who met AKI criteria within the first 2 d following ARDS onset), we classified the study population into two groups: "late AKI" and "no AKI." The "late AKI" group included patients who developed AKI more than 2 days but no longer than 7 days following ARDS onset. None. Of 5367 patients with ARDS initially enrolled in trials, 2960 patients were included in the main analysis. Late AKI developed in 1000 patients (33.8%). After controlling for confounders, baseline driving pressure was independently associated with development of late AKI (each 1 sd increase in driving pressure was associated with a 35% increase in the odds of late AKI [odds ratio, 1.35; 95% CI, 1.15-1.58]). This result persisted in the sensitivity analysis, which did not exclude patients with early AKI, and in the sensitivity analysis, which included patients who developed AKI later than 7 days following ARDS onset. There was a threshold of driving pressure equal to 15 cm H 2 O for its association with development of late AKI. Driving pressure was associated with subsequent development of AKI in patients with ARDS suggesting that injurious mechanical ventilation may lead to AKI.

Severe Acute Pancreatitis-Associated Lung Injury: A Comprehensive Quadruple Analysis of Animal Models.

Severe acute pancreatitis (SAP) is a common clinical acute abdominal disorder. One of the critical complications of SAP is acute lung injury (ALI), which is the leading cause of high mortality in SAP patients. Establishing an animal model is pivotal in understanding of SAP pathogenesis and treatment. The 5% Sodium taurocholate (STC) solution was administered to induce severe acute pancreatitis-associated acute lung injury (SAP-ALI). Additionally, a Sham operation group (SO) and a Normal saline control group (NS) were included in the study. Nine time-point subgroups were established at 3, 6, 9, 12, 18, 24, 36, 48, and 72 h post-treatment. Lung injury was comprehensively assessed from four perspectives: physiological dysfunction, inflammatory response, alterations in vascular permeability, and tissue damage. Ultimately, the model was constructed according to the previously established methodology. High-resolution micro-computed tomography (micro-CT) for small animals was employed to evaluate the extent of lung injury. The SAP-ALI animal model was effectively induced using a 5% sodium taurocholate solution, with the peak lung injury score observed at 24h post-induction. Histological examination of the entire pancreas in the micro-CT group revealed more pronounced pancreatic injury in the pancreatic head region at the 24-h time point following model establishment. Upon horizontal comparison of the micro-CT images with the complete lung pathology images, a close correlation between the injury sites was observed. At the 24-h time point in the SAP animal model, the lung injury manifestations and diverse indicators were notably robust. The application of micro-CT emerged as a pivotal non-invasive modality for diagnosing lung injury in SAP-ALI animal models.

Cimifugin ameliorates ulcerative colitis-related lung injury by modulating the JAK1/STAT1 signaling pathway and macrophage M1 polarization

IntroductionUlcerative colitis (UC)-related lung injurys is a commonly overlooked extraintestinal manifestation and there are currently no drugs with definitive efficacy available. Cimifugin has been found to inhibit aberrant inflammation and oxidative stress, but its efficacy in UC-related lung injurys has not yet been demonstrated.MethodsThis study explored the effects of Cimifugin on UC-related lung injurys using RNA-seq in combination with 16S rRNA sequencing.ResultsCimifugin significantly ameliorated symptoms and attenuated colon and lung injury in a UC mouse model, restored the integrity of the intestinal and lung epithelial barriers, and suppressed lung inflammation, which was achieved by inhibiting the JAK1/STAT1 pathway and the M1 macrophage-mediated inflammatory state in the colon and lungs, as well as by improving the homeostasis of the intestinal microbiota. DiscussionCimifugin ameliorates UC-associated lung injury by modulating the JAK1/STAT1 pathway and macrophage M1 polarization.

Costunolide: Targeting endothelial cell PANoptosis to mitigate lung injury in acute pancreatitis mice.

Costunolide: Targeting endothelial cell PANoptosis to mitigate lung injury in acute pancreatitis mice.

MiR-125b-5p ameliorates ventilator-induced lung injury in rats by suppressing ferroptosis via the regulation of the Keap1/Nrf2/GPX4 signaling pathway

Ventilator induced lung injury (VILI) is caused by improper use of mechanical ventilation, and its pathogenesis remains unclear. The aim of this study was to establish animal and cell models of VILI, and to explore the mechanism of miR-125b-5p in alleviating VILI by inhibiting ferroptosis through targeted regulation of Keap1/Nrf2/GPX4 axis. Firstly, ferrostain-1(Fer-1), a ferroptosis inhibitor, was used to confirm that ferroptosis was involved in the progression of VILI. Secondly, overexpression and knockdown of miR-125b-5p were performed to validate its function; Further, mechanistically, miR-125b-5p targets negatively regulated Keap1 to activate Nrf2 and then increased the expression of GPX4, thereby inhibiting the occurrence of ferroptosis. Finally, the rescue experiment shows, overexpression of Keap1 and use of the GPX4 inhibitor RSL3 reversed the miR-125b-5p effect, respectively. Through real-time quantitative polymerase chain reaction (qRT-PCR), western blotting (WB), immunofluorescence (IF), hematoxylin and eosin (H&E), and iron death related factor detection, it was confirmed that, overexpression of miR-125b-5p upregulates ferroptosis inhibitory protein and downregulates ferroptosis promoting protein, leading to alleviation of lung injury. However, overexpression of Keap1 and RSL3 reverses the effect of miR-125b-5p, respectively. Therefore, miR-125b-5p can inhibit ferroptosis and alleviate lung injury in VILI rats by targeting the Keap1/Nrf2/GPX4 axis, miR-125b-5p may be a potential intervention target for VILI.

Nicotinamide mononucleotide mitigates hyperoxia-aggravated septic lung injury via the GPx4-mediated anti-ferroptosis signaling pathway in alveolar epithelial cells.

Nicotinamide mononucleotide mitigates hyperoxia-aggravated septic lung injury via the GPx4-mediated anti-ferroptosis signaling pathway in alveolar epithelial cells.

Fruit of Physalis angulata L. and anti-inflammatory potential: An in silico, in vitro, and in vivo study focusing on PFKFB3.

Fruit of Physalis angulata L. and anti-inflammatory potential: An in silico, in vitro, and in vivo study focusing on PFKFB3.

Human placental mesenchymal stem cell-derived exosomes carrying hsa-let-7i-5p mitigate lung injury in a murine model of aspiration pneumonia.

Aspiration pneumonia (AP), which can be caused by gastric content inhalation into the lower airways, causes acute lung injury (ALI) through complex mechanisms, including inflammation, oxidative stress, and apoptosis. Here, we evaluated the efficacy of exosomes derived from human placental mesenchymal stem cells (hpMSCs) in mitigating ALI in a murine model of AP. We also investigated the role of hsa-let-7i-5p, the most abundant miRNA in hpMSC-derived exosomes, in this respect. Adult male C57BL/6 mouse AP models were administered hpMSC-derived exosomes (APExo group) or phosphate-buffered saline (AP group) intra-tracheally. After 48 h, the mice were euthanized and evaluated. The effects of hsa-let-7i-5p were assessed by specific inhibition or overexpression. Compared with the APExo group, the AP group exhibited significantly greater ALI, as evidenced by histological damage, increased lung injury scores, impaired lung function, increased leukocyte infiltration, and elevated tissue edema (all P < 0.05). The untreated AP group also showed more inflammation, characterized by nuclear factor-κB upregulation, macrophage M1 polarization, and cytokine level elevation (tumor necrosis factor-α, interleukin-1β, and interleukin-6), as well as increased oxidation and activation of the apoptosis pathway (all P < 0.05). Notably, the therapeutic effects of hpMSC-derived exosomes were compromised by specific inhibition of hsa-let-7i-5p. Furthermore, engineered exosomes derived from genetically modified RAW264.7 overexpressing hsa-let-7i-5p demonstrated therapeutic effects against AP similar to those obtained with hpMSC-derived exosomes. In a murine AP model, intra-tracheal administration of hpMSC-derived exosomes has ALI-mitigating effects, involving inflammation, oxidation, and apoptosis modulation, with hsa-let-7i-5p playing a pivotal mediating role.

OTUD1 inhibits macrophage ferroptosis via regulation of AMPK and GSK3β/β-catenin signaling pathways exerting protective effects in sepsis-induced acute lung injury.

OTUD1 inhibits macrophage ferroptosis via regulation of AMPK and GSK3β/β-catenin signaling pathways exerting protective effects in sepsis-induced acute lung injury.

A novel rabbit model of severe ARDS: Synergistic effects of acid aspiration and harmful mechanical ventilation.

A novel rabbit model of severe ARDS: Synergistic effects of acid aspiration and harmful mechanical ventilation.

NLRP3 regulates macrophage function by M-CSF/M-CSFR signaling in acute radiation-induced lung injury.

NLRP3 regulates macrophage function by M-CSF/M-CSFR signaling in acute radiation-induced lung injury.

Mesenchymal stromal cell secretome reduces lung injury and thrombo-inflammation induced by SARS-CoV-2 spike protein

Severe COVID-19 is characterized by thrombo-inflammatory processes within the lung microvasculature. In pursuit of effective treatments, clinical studies explored mesenchymal stromal cells (MSCs) as a promising approach due to their anti-inflammatory, immunomodulatory, and regenerative properties, through their paracrine action.Here, we tested the conditioned medium (CM) derived from human umbilical cord (UC)-MSCs in acute lung injury induced by the spike protein subunit 1 (S1) in ACE2-humanized male mice. Injection of CM significantly limited S1-induced lung injury, edema, and fibrosis. This was associated with reduced vascular dysfunction, in terms of restored thrombomodulin levels and decreased von Willebrand (vWF) expression. By preserving endothelial glycocalyx, CM reduced complement C3 accumulation, favoring factor H binding on the lung microvasculature. Reduced oxidative stress, nuclear NF-κB p65 accumulation, and inflammatory cell infiltration were also observed in response to CM in S1-injected mice.In vitro, CM counteracted thrombo-inflammation by preserving thrombomodulin, as well as limiting vWF expression, due to endothelial glycocalyx recovery. CM reduced nuclear translocation of NF-κB p65 and its downstream targets, ICAM-1 and P-selectin, translating in decreased C3 deposits, platelet aggregation, and leukocyte adhesion on S1-challenged endothelial cells.Collectively, these data indicate that UC-MSC-derived secretome represents a promising therapy in COVID-19 due to its potent anti-thrombotic and anti-inflammatory effects on lung microcirculation.