The adverse health consequences of air pollution are well recognized and range from minor upper respiratory system irritation to severe chronic lung disease. The identity and mechanisms of these pollutants, as well as how toxicity is influenced by additional risk factors are unclear. This study elucidates the relationship between air pollution and microbial agents and explores the mechanisms by which the two stimuli interact to cause adverse health effects with important public health relevance. Mycoplasma fermentans is a species of atypical bacteria with immune-regulatory properties and potential to establish chronic latent infections. Particulate matter (PM) is a complex and diverse component of air pollution associated with adverse health effects. The hypothesis of this study is that M. fermentans infection modulates the cellular responses induced by exposure to residual oil fly ash (ROFA), a type of PM particularly rich in metals. Using human lung fibroblasts (HLF) as an in vitro model I measured the release of the immune-modulating cytokine interleukin-6 (IL-6) as a biomarker of stress-induced cell activation after exposure to various chemical and microbial challenges alone or together. The synergistic interaction between live M. fermentans and ROFA to stimulate IL-6 release and gene expression in HLF was demonstrated. This effect was specific for PM that contains high amounts of water-soluble metal and was recapitulated when NiSO4 was substituted for ROFA. The potentiating effect of live infection was mimicked by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2 agonist. Experiments with consecutive singular exposures to MALP-2 and NiSO4 revealed that pre-treatment of cells with NiSO4 facilitated MALP-2-induced IL-6 production, while pre-exposure to MALP-2 failed to influence the response to Ni. Facilitation of MALP-2 response by NiSO4 depended, in part, upon Ni-induced activation of the ERK1/2 MAP kinase. These interactive effects were studied at the level of gene transcription using a series of IL-6 promoter-luciferase reporter constructs and mutants.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11152005-130323 |
| Date | 06 February 2006 |
| Creators | Gao, Fei |
| Contributors | Bruce R. Pitt PhD, Simon Barrat-Boyes BVSc, PhD, James P. Fabisiak PhD, Koichi Takimoto PhD, Barry R. Stripp PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11152005-130323/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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