title: Hypoxia-Induced Epithelial-Mesenchymal Transition Is Involved in Bleomycin-Induced Lung Fibrosis.
abstract: Pulmonary fibrosis is a severe disease that contributes to the morbidity and mortality of a number of lung diseases. However, the molecular and cellular mechanisms leading to lung fibrosis are poorly understood. This study investigated the roles of epithelial-mesenchymal transition (EMT) and the associated molecular mechanisms in bleomycin-induced lung fibrosis. The bleomycin-induced fibrosis animal model was established by intratracheal injection of a single dose of bleomycin. Protein expression was measured by Western blot, immunohistochemistry, and immunofluorescence. Typical lesions of lung fibrosis were observed 1 week after bleomycin injection. A progressive increase in MMP-2, S100A4, α-SMA, HIF-1α, ZEB1, CD44, phospho-p44/42 (p-p44/42), and phospho-p38 MAPK (p-p38) protein levels as well as activation of EMT was observed in the lung tissues of bleomycin mice. Hypoxia increased HIF-1α and ZEB1 expression and activated EMT in H358 cells. Also, continuous incubation of cells under mild hypoxic conditions increased CD44, p-p44/42, and p-p38 protein levels in H358 cells, which correlated with the increase in S100A4 expression. In conclusion, bleomycin induces progressive lung fibrosis, which may be associated with activation of EMT. The fibrosis-induced hypoxia may further activate EMT in distal alveoli through a hypoxia-HIF-1α-ZEB1 pathway and promote the differentiation of lung epithelial cells into fibroblasts through phosphorylation of p38 MAPK and Erk1/2 proteins.
authors.affiliation: Department of Anesthesiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China; Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Jun-mei
authors.initials: JM
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Su-mei
authors.initials: SM
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects* / Q000494:pharmacology; D002460:Cell Line; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology
chemical_list: D001761:Bleomycin
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