| 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
|
| Resource |
| Mice |
RBRC01834 |
