Cell type-specific effect of hypoxia and platelet-derived growth factor-BB on extracellular matrix turnover and its consequences for lung remodeling.
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.
Karakiulakis
George
G
Department of Pharmacology, School of Medicine, Aristotle University, GR-54124 Thessaloniki, Greece, and Pulmonary Cell Research and Pneumology, University Hospital Basel, CH-4031 Basel, Switzerland.
Papakonstantinou
Eleni
E
Aletras
Alexios J
AJ
Tamm
Michael
M
Roth
Michael
M
D000077214:Becaplermin; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D024042:Collagen Type I; D004792:Enzyme Precursors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077214:Becaplermin; D018093:Gelatinases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9