Cell type-specific effect of hypoxia and platelet-derived growth factor-BB on extracellular matrix turnover and its...

Hypoxia is associated with extracellular matrix remodeling in several inflammatory lung diseases, such as fibrosis, chronic obstructive pulmonary disease, and asthma. In a human cell culture model, we assessed whether extracellular matrix modification by hypoxia and platelet-derived growth factor (PDGF) involves the action of matrix metalloproteinases (MMPs) and thereby affects cell proliferation. Expression of MMP and its activity were assessed by zymography and enzyme-linked immunosorbent assay in human lung fibroblasts and pulmonary vascular smooth muscle cells (VSMCs), and synthesis of soluble collagen type I was assessed by enzyme-linked immunosorbent assay. In both cell types, hypoxia up-regulated the expression of MMP-1, -2, and -9 precursors without subsequent activation. MMP-13 was increased by hypoxia only in fibroblasts. PDGF-BB inhibited the synthesis and secretion of all hypoxia-dependent MMP via Erk1/2 mitogen-activated protein (MAP) kinase activation. Hypoxia and PDGF-BB induced synthesis of soluble collagen type I via Erk1/2 and p38 MAP kinase. Hypoxia-induced cell proliferation was blocked by antibodies to PDGF-BB or by inhibition of Erk1/2 but not by the inhibition of MMP or p38 MAP kinase in fibroblasts. In VSMCs, hypoxia-induced proliferation involved Erk1/2 and p38 MAP kinases and was further increased by fibroblast-conditioned medium or soluble collagen type I via Erk1/2. In conclusion, hypoxia controls tissue remodeling and proliferation in a cell type-specific manner. Furthermore, fibroblasts may affect proliferation of VSMC indirectly by inducing the synthesis of soluble collagen type I.