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ToxSci Advance Access published online on October 1, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn208
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Nickel and the Microbial Toxin, MALP-2, Stimulate Pro-Angiogenic Mediators from Human Lung Fibroblasts via a HIF-1{alpha} and COX-2-mediated pathway

Kelly A. Brant* and James P. Fabisiak*

* Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15219-3130 USA; kab124{at}pitt.edu, fabs{at}pitt.edu

Corresponding Author: Kelly Brant, MPH, Ph.D., 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, Phone: 412-624-0103, FAX: (412) 624-9361, Email: kab124{at}pitt.edu.

Received July 10, 2008; revision received September 26, 2008; accepted September 26, 2008


  Abstract

HIF-1{alpha} and 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 (HLF) treated with mixed exposures to chemical and microbial stimuli, HIF-1{alpha} stabilization plays a pivotal role in the induction of COX-2 mRNA and protein, driving the release of VEGF and pro-angiogenic and pro-fibrotic chemokines. Upon co-stimulation with Ni and the mycoplasma-derived lipopeptide 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-1{alpha} protein in HLF, which was further enhanced in the presence of MALP-2. Depletion of HIF-1{alpha} 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 pro-fibrotic phenotype in HLF. Moreover, these findings reveal a potential role for HIF-1{alpha} in mediating chemical-induced alterations in cellular response to microbial stimuli, modulating pulmonary inflammation and its consequences such as fibrosis and angiogenesis.

Key Words: HIF-1{alpha}; COX-2; fibroblasts; inflammation; Ni; MALP-2.


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