主催: 第94回日本薬理学会年会
会議名: 第94回日本薬理学会年会
回次: 94
開催地: Sapporo
開催日: 2021/03/08 - 2021/03/10
Background: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with apoor prognosis. Fibroblast pro- liferation amplifies extracellular matrixdeposition and increases angiogenesis. Vascular endothelial growth factor (VEGF)is one of the most potent angiogenic factors. VEGF interacts with VEGF receptors(VEGFR1 and VEGFR2). A previous study showed that VEGFR1 tyrosine kinase (TK)signaling induced blood flow recovery mediated by bone marrow (BM)-derived stemcells. We hypothesized that VEGFR1-TK signaling might be related topulmonary fibrosis.
Material and methods: Six-week-old male C57Bl/6 wild-type (WT) mice and VEGFR1 TKknockout mice (TKKO mice) were treated with a single intratracheal injection ofbleomycin (BLM; 0.1 μg in 50 μl saline) or vehicle (saline; 50 μl).Lung fibrosis was evaluated by histology, real-time PCR and ELISA forpro-fibrotic factors, and assessment of lung mechanics.
Results: The fibrotic area in the lung and the lung elastance were significantlyreduced in TKKO mice (P < 0.01). The expression of the fibrosis-relatedfactors type I collagen, S100A4, and transforming growth factor (TGF)-β was alsosignificantly reduced in TKKO mice on day 21 after BLM injection. TKKO mice alsohad significantly lower levels of stromal cell-derived factor (SDF)-1 in thelungs and plasma on days 14 and 21 after BLM treatment (P < 0.05). Moreover,the expression of C-X-C chemokine receptor type 7 (CXCR7) and CXCR4, thereceptors for SDF-1, was also suppressed in TKKO mice. Immunohistochemicalanalysis showed that treat- ment with a CXCR4 antibody decreased theaccumulation of VEGFR1+ cells in the lung in WT mice but not in TKKO mice.
Conclusion: These results suggest that VEGFR1 TK signaling promotes BLM-inducedpulmonary fibrosis by ac- tivating the SDF-1/CXCR4 axis in infiltratingVEGFR1+ cells.