title: Nickel and the microbial toxin, MALP-2, stimulate proangiogenic mediators from human lung fibroblasts via a HIF-1alpha and COX-2-mediated pathway.
abstract: Hypoxia-inducible factor (HIF-1alpha) and cyclooxygenase-2 (COX-2) have been implicated in the regulation of inflammatory-like processes that lead to angiogenesis and fibrotic disorders. Here we demonstrate that in human lung fibroblasts (HLFs) treated with mixed exposures to chemical and microbial stimuli, HIF-1alpha stabilization plays a pivotal role in the induction of COX-2 mRNA and protein, driving the release of vascular endothelial growth factor (VEGF) and proangiogenic and profibrotic chemokines. Upon costimulation with Ni and the mycoplasma-derived lipopeptide macrophage-activating lipopeptide-2 (MALP-2), there was a synergistic induction of CXCL1 and CXCL5 mRNA and protein release from HLF, as well as an enhanced response in VEGF compared to either stimulus alone. Consistent with our previous findings that Ni and MALP-2 stimulates the induction of CXCL8 via a COX-2-mediated pathway, CXCL1, CXCL5, and VEGF release were also regulated by COX-2. Ni induced the stabilization of HIF-1alpha protein in HLF, which was further enhanced in the presence of MALP-2. Depletion of HIF-1alpha using siRNA blocked COX-2 induction by Ni and MALP-2 along with the release of VEGF, CXCL1, CXCL5, and CXCL8. Our results indicate that Ni and MALP-2 interact to promote an angiogenic profibrotic phenotype in HLF. Moreover, these findings reveal a potential role for HIF-1alpha in mediating chemical-induced alterations in cellular response to microbial stimuli, modulating pulmonary inflammation and its consequences such as fibrosis and angiogenesis.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15219-3130, USA. kab124@pitt.edu
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Brant
authors.forename: James P
authors.initials: JP
authors.lastname: Fabisiak
mesh_terms: D000704:Analysis of Variance; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009532:Nickel / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D019743:Chemokines, CXC; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D055666:Lipopeptides; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D009532:Nickel; C106335:macrophage stimulatory lipopeptide 2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human