Nickel and the Microbial Toxin, MALP-2, Stimulate Proangiogenic Mediators from Human Lung Fibroblasts via a HIF-1{alpha} and COX-2-Mediated Pathway |
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Authors: | Brant Kelly A; Fabisiak James P |
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Institution: | Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15219-3130
1 To whom correspondence should be addressed at University of Pittsburgh Graduate School of Public Health, Department of Environmental and Occupational Health, Bridgeside Point, 100 Technology Drive, Room 327, BRIDG, Pittsburgh, PA 15219-3130. Fax: (412) 624-9361. E-mail: kab124{at}pitt.edu. |
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Abstract: | Hypoxia-inducible factor (HIF-1 ) and cyclooxygenase-2 (COX-2)have been implicated in the regulation of inflammatory-likeprocesses that lead to angiogenesis and fibrotic disorders.Here we demonstrate that in human lung fibroblasts (HLFs) treatedwith mixed exposures to chemical and microbial stimuli, HIF-1 stabilization plays a pivotal role in the induction of COX-2mRNA and protein, driving the release of vascular endothelialgrowth factor (VEGF) and proangiogenic and profibrotic chemokines.Upon costimulation with Ni and the mycoplasma-derived lipopeptidemacrophage-activating lipopeptide-2 (MALP-2), there was a synergisticinduction of CXCL1 and CXCL5 mRNA and protein release from HLF,as well as an enhanced response in VEGF compared to either stimulusalone. Consistent with our previous findings that Ni and MALP-2stimulates 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-1 protein in HLF, whichwas further enhanced in the presence of MALP-2. Depletion ofHIF-1 using siRNA blocked COX-2 induction by Ni and MALP-2 alongwith the release of VEGF, CXCL1, CXCL5, and CXCL8. Our resultsindicate that Ni and MALP-2 interact to promote an angiogenicprofibrotic phenotype in HLF. Moreover, these findings reveala potential role for HIF-1 in mediating chemical-induced alterationsin cellular response to microbial stimuli, modulating pulmonaryinflammation and its consequences such as fibrosis and angiogenesis. |
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Keywords: | HIF-1 " target="_blank">gif" ALT="{alpha}" BORDER="0"> COX-2 fibroblasts inflammation Ni MALP-2 |
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