Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin.
Akina KawaraRyo MizutaMasayoshi FujisawaToshihiro ItoChunning LiKaoru NakamuraCuiming SunMasaki KuwabaraMasahiro KitabatakeTeizo YoshimuraAkihiro MatsukawaPublished in: Scientific reports (2020)
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.
Keyphrases
- induced apoptosis
- signaling pathway
- pulmonary fibrosis
- cell cycle arrest
- oxidative stress
- high fat diet induced
- cell proliferation
- bone marrow
- type diabetes
- stem cells
- transcription factor
- dendritic cells
- acute myeloid leukemia
- drug delivery
- small molecule
- mouse model
- diabetic rats
- high glucose
- mesenchymal stem cells
- combination therapy
- replacement therapy
- newly diagnosed
- amino acid
- endothelial cells
- cancer therapy
- lps induced