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Activin-A production by recruited alveolar macrophages exacerbates pulmonary fibrosis following acute lung injury

ABSTRACT: Background: Acute respiratory distress syndrome (ARDS) is a complicated pathological cascade process of excessive pulmonary inflammation and alveolar epithelial cells apoptosis which results in respiratory dysfunction and failure. Some ARDS can result in more severe state of pulmonary fibrosis, referred to as post-injury lung fibrosis. The mortality and incidence rate of ARDS are particularly high when it leads to continuing alveolar and interstitial fibrosis, which requires urgent treatment and appropriate management. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model has been widely implemented for studying ARDS in human. Here, we found alterations in the alveolar macrophage (AM) profile in such a mouse model. Specifically, activin-A produced by dominantly recruited AMs (recAMs), was noted to be implicated in the processing of post-injury lung fibrosis. Methods: ALI animal model in C57BL/6 mice was established via 3.5mg/kg LPS intra-tracheal administration. Single-cell RNA (scRNA) sequencing was used for detailed classification and functional characterization of lung macrophages. in vivo experiments, we evaluated the role that activin-A plays in post-injury lung fibrosis in an ALI mouse model using ELISA (Enzyme-linked immunosorbent assay), histological staining methods and immunofluorescence. in vitro experiments, we analyzed the effect of activin-A on MLE-12 cells and bone marrow-derived macrophages (BMDMs) using western blot (WB), qPCR (quantitative real-time PCR), RNA-seq (RNA sequencing) and immunofluorescence. Results: Our findings revealed that recAMs replaced tissue resident alveolar macrophages (TRAMs) as a dominant macrophage population in the setting of ALI. The result of GO (gene ontology) analysis suggested that activin-A was associated with wound healing and SMAD (suppressor of mothers against decapentaplegic) protein signaling pathways. Immunofluorescence results revealed that the receptor of activin-A mainly localized to alveolar epithelial cells and macrophages. Subsequently, activin-A was specifically found to drive MLE-12 to mesenchymal cell transformation via the TGF-β (transforming growth factor-β)/SMAD signaling. Moreover, the results of transcriptome analysis and WB confirmed that activin-A could enhance the concerted activity of Hippo and TGF-β/SMAD pathways in BMDMs, leading to an increased expression of pro-fibrotic mediator. At the same time, yes-associated protein (YAP) and transcriptional coactivated with PDZ-binding motif (TAZ) proteins were found to drive BMDM activin-A expression, which could generate a positive feedback mechanism that perpetuates fibrosis. Conclusion: Our findings revealed that activin-A is involved in the pathological mechanisms in post-injury lung fibrosis by promoting EMT (epithelial–mesenchymal transition) and the formation of an underlying profibrotic positive feedback loop in recAMs. Activin-A is thus a potential therapeutic target for developing ALI and ALI-associated pulmonary fibrosis therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE280364 | GEO | 2025/10/28

REPOSITORIES: GEO

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Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs characterized by increased permeability of the alveolar-capillary membrane with subsequent interstitial/alveolar edema and diffuse alveolar damage. ALI/ARDS can be the results of either direct or indirect lung injury, with pneumonia being the most common direct pulmonary insult and sepsis the most common extra-pulmonary cause. In this study, we employed the murine lipopolysaccharide (LPS)-induced direct and indirect lung injury model to explore the pathogenic mechanisms of pulmonary and extra-pulmonary ARDS, using an unbiased, discovery and quantitative proteomic approach. A total of 1,017 proteins were both identified and quantified in bronchoalveolar lavage fluid (BALF) from control, intratracheal LPS (I.T. LPS, 0.1 mg/kg) and intraperitoneal LPS (I.P. LPS, 5 mg/kg) treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Among them, molecules related to bronchial and type II alveolar epithelial cell functions including cell adhesion molecule 1 and surfactant protein B were reduced, whereas lactotransferrin and resistin like alpha involved in lung innate immunity were upregulated in both LPS groups. Proteomic profiling also identified significant differences in BALF proteins between I.T. and I.P. LPS groups. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS, however, the magnitude of activation is much greater in I.T. LPS group compared to I.P. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. LPS but suppressed by I.P. LPS. In addition, CXCL15 (also known as lungkine) was also up-regulated by I.T LPS but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities as well as significant differences in BALF protein expression profiles in LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury results in suppression of select components of lung innate immunity, which could contribute to the so-called “immunoparalysis” in sepsis patients.

Project description:Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure. The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts. The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega). In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco. The Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page <a href="study.cgi?study_id=phs000631">phs000631</a> ARDSnet iSPAAR Consortium. <ul> <li><a href="study.cgi?study_id=phs000334">phs000334</a> ESP_LungGO_ALI </li> <li><a href="study.cgi?study_id=phs000686">phs000686</a> ALI_GeneticRisk </li> </ul>

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Activin-A production by recruited alveolar macrophages exacerbates pulmonary fibrosis following acute lung injury

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