RRC ID 61626
Author Kawara A, Mizuta R, Fujisawa M, Ito T, Li C, Nakamura K, Sun C, Kuwabara M, Kitabatake M, Yoshimura T, Matsukawa A.
Title Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin.
Journal Sci Rep
Abstract The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2-/- mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2-/- lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2-/- and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2-/- fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2-/- mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.
Volume 10(1)
Pages 16490
Published 2020-10-5
DOI 10.1038/s41598-020-73752-3
PII 10.1038/s41598-020-73752-3
PMID 33020583
PMC PMC7536438
MeSH Animals Bleomycin / pharmacology* Cell Proliferation / drug effects Cell Proliferation / physiology* Cells, Cultured Epithelial Cells / drug effects Epithelial Cells / metabolism* Fibroblasts / drug effects Fibroblasts / metabolism Lipopolysaccharides / metabolism Lung / drug effects Lung / metabolism* MAP Kinase Signaling System / drug effects MAP Kinase Signaling System / physiology Macrophages / drug effects Macrophages / metabolism Mice Mice, Inbred C57BL Myeloid Cells / drug effects Myeloid Cells / metabolism Pulmonary Fibrosis / chemically induced* Pulmonary Fibrosis / metabolism* Repressor Proteins / metabolism* Tumor Necrosis Factor-alpha / metabolism
IF 3.998
Mice RBRC01834