RRC ID 62328
著者 Takenouchi Y, Kitakaze K, Tsuboi K, Okamoto Y.
タイトル Growth differentiation factor 15 facilitates lung fibrosis by activating macrophages and fibroblasts.
ジャーナル Exp Cell Res
Abstract Lung fibrosis is a devastating disease characterized by fibroblast accumulation and extracellular matrix deposition in lungs. However, its molecular and cellular pathogenesis is not fully understood and the current therapeutic strategies are ineffective. Bleomycin-induced lung fibrosis is the most widely used experimental model for research aimed at in-depth analysis of lung fibrosis mechanisms. The present study aimed to analyse the effects of growth differentiation factor 15 (GDF15), which is associated with many diseases, in lung fibrosis. GDF15 mRNA expression was elevated in the lungs of bleomycin-treated mice, revealed by comprehensive gene analysis. Its protein levels were also increased in the lungs, bronchoalveolar lavage fluid, and plasma obtained from bleomycin-treated mice as compared to those in saline-treated mice. Bleomycin administration in mice resulted in a marked increase in senescence-associated β-galactosidase-positive and p16INK4a-positive lung structural cells including alveolar epithelial cells and macrophages. Immunohistochemical staining using anti-GDF15 antibody and increased mRNA expression of GDF15 in bleomycin-induced senescent A549 cells indicated that GDF15 is produced from alveolar epithelial cells undergoing bleomycin-induced cellular senescence. GDF15 was also implicated in the augmentation of interleukin-4/interleukin-13-induced mRNA expression of M2 markers including arginase 1 and chitinase-3-like protein and was also responsible for increased α-smooth muscle actin expression through the ALK5-Smad2/3 pathway in WI-38 lung fibroblasts. Therefore, GDF15 secreted from senescent alveolar epithelial cells might act as a profibrotic factor through activation of M2 macrophages and fibroblasts. This implies that GDF15 could be a potential therapeutic target and a predictor of lung fibrosis progression.
巻・号 391(2)
ページ 112010
公開日 2020-6-15
DOI 10.1016/j.yexcr.2020.112010
PII S0014-4827(20)30232-9
PMID 32305327
MeSH A549 Cells Animals Antibiotics, Antineoplastic / toxicity Bleomycin / toxicity* Cellular Senescence Epithelial-Mesenchymal Transition* Fibroblasts / drug effects Fibroblasts / metabolism Fibroblasts / pathology* Growth Differentiation Factor 15 / genetics Growth Differentiation Factor 15 / metabolism* Humans Macrophages / drug effects Macrophages / metabolism Macrophages / pathology* Mice Mice, Inbred C57BL Pulmonary Fibrosis / chemically induced Pulmonary Fibrosis / metabolism Pulmonary Fibrosis / pathology* Signal Transduction
IF 3.383
リソース情報
ヒト・動物細胞 A549(RCB0098)