Hypoxic mast cells accelerate the proliferation, collagen accumulation and phenotypic alteration of human lung fibroblasts

Pulmonary vascular remodeling and fibrosis are the critical pathological characteristics of hypoxic pulmonary hypertension. Our previous study demonstrated that hypoxia is involved in the functional alteration of lung fibroblasts, but the underlying mechanism has yet to be fully elucidated. The aim of the present study was to investigate the effect of mast cells on the proliferation, function and phenotype of fibroblasts under hypoxic conditions. Hypoxia facilitated proliferation and the secretion of proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, in human mast cells (HMC-1). RNA sequencing identified 2,077 upregulated and 2,418 downregulated mRNAs in human fetal lung fibroblasts (HFL-1) cultured in hypoxic conditioned medium from HMC-1 cells compared with normoxic controls, which are involved in various pathways, including extracellular matrix organization, cell proliferation and migration. Conditioned medium from hypoxic HMC-1 cells increased the proliferation and migration capacity of HFL-1 and triggered phenotypic transition from fibroblasts to myofibroblasts. A greater accumulation of collagen type I and III was also observed in an HFL-1 cell culture in hypoxic conditioned medium from HMC-1 cells, compared with HFL-1 cells cultured in normoxic control medium. The expression of matrix metalloproteinase (MMP)-9 and MMP-13 was upregulated in HFL-1 cells grown in hypoxic conditioned medium from HMC-1 cells. Similar pathological phenomena, including accumulation of mast cells, activated collagen metabolism and vascular remodeling, were observed in a hypoxic rat model. The results of the present study provide direct evidence that the multiple effects of the hypoxic microenvironment and mast cells on fibroblasts contribute to pulmonary vascular remodeling, and this process appears to be among the most important mechanisms underlying hypoxic pulmonary hypertension.