M2 macrophage accumulation contributes to pulmonary fibrosis, vascular dilatation, and hypoxemia in rat hepatopulmonary syndrome. Issue 11 (27th May 2021)

• Record Type: Journal Article
• Authors: Chen, Bing; Yang, Yong; Yang, Congwen; Duan, Jiaxiang; Chen, Lin; Lu, Kaizhi; Yi, Bin; Chen, Yang; Xu, Duo; Huang, He
• Is Part Of: Journal of cellular physiology. Volume 236:Issue 11(2021)
• Page Start: 7682
• Page End: 7697
• Publication Date: 2021-05-27
• Subjects: fibrosis -- granulocyte‐macrophage colony stimulating factor -- hepatopulmonary syndrome -- macrophages -- monocyte chemoattractant protein 1 -- neutrophils; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30420
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Hepatopulmonary syndrome (HPS) markedly increases the mortality of patients. However, its pathogenesis remains incompletely understood. Rat HPS develops in common bile duct ligation (CBDL)‐induced, but not thioacetamide (TAA)‐induced cirrhosis. We investigated the mechanisms of HPS by comparing these two models. Pulmonary histology, blood gas exchange, and the related signals regulating macrophage accumulation were assessed in CBDL and TAA rats. Anti‐polymorphonuclear leukocyte (antiPMN) and anti‐granulocyte‐macrophage colony stimulating factor (antiGM‐CSF) antibodies, clodronate liposomes (CL), and monocyte chemoattractant protein 1 (MCP1) inhibitor (bindarit) were administrated in CBDL rats, GM‐CSF, and MCP1 were administrated in bone marrow‐derived macrophages (BMDMs). Pulmonary inflammatory cell recruitment, vascular dilatation, and hypoxemia were progressively developed by 1 week after CBDL, but only occurred at 4 week after TAA. Neutrophils were the primary inflammatory cells within 3 weeks after CBDL and at 4 week after TAA. M2 macrophages were the primary inflammatory cells, meantime, pulmonary fibrosis, GM‐CSFR, and CCR2 were specifically increased from 4 week after CBDL. AntiPMN antibody treatment decreased neutrophil and macrophage accumulation, CL or the combination of antiGM‐CSF antibody and bindarit treatment decreased macrophage recruitment, resulting in pulmonary fibrosis, vascular dilatation, and hypoxemia in CBDL rats alleviated. The combination treatment of GM‐CSF and MCP1 promoted cell migration, M2 macrophage differentiation, and transforming growth factor‐β1 (TGF‐β1) production in BMDMs. Conclusively, our results highlight neutrophil recruitment mediates pulmonary vascular dilatation and hypoxemia in the early stage of rat HPS. Further, M2 macrophage accumulation induced by GM‐CSF/GM‐CSFR and MCP1/CCR2 leads to pulmonary fibrosis and promotes vascular dilatation and hypoxemia, as a result, HPS develops. Abstract : Comparing hepatopulmonary syndrome (HPS) and non‐HPS models, we illustrated experimental HPS is associated with initial neutrophil recruitment and latter M2 macrophage accumulation. Neutrophil recruitment causes pulmonary vascular dilatation and hypoxemia. M2 macrophage accumulation, which induced by granulocyte‐macrophage colony stimulating factor (GM‐CSF) and monocyte chemoattractant protein 1 (MCP1), causes pulmonary fibrosis, and enhances vascular dilatation and hypoxemia.