Diverse stressors of chemical and microbial origin can produce lung inflammation and adverse cardio-respiratory health effects. Effects of single agents have been well described clinically and experimentally, however, we hypothesize that chemical and microbial stress can interact to produce a response that is greater than that predicted by the response to single agents alone. Metals, such as nickel (Ni) derived from atmospheric particulate matter (PM) are important components of ambient air pollution associated with adverse health effects. Mycoplasma are a class of microorganism that potentially can produce chronic/persistent/latent infections within the lung with minimal signs of infection. We hypothesize that the presence of microorganisms like mycoplasma will potentiate the inflammatory/immunomodulating potential of chemical stress and, thus, act as co-factors in the genesis or exacerbation of chronic inflammatory and fibrotic lung disease following exposure to PM-derived metals. We will utilize M. fermentans as a prototypic organism capable of latent/subclinical infection or colonization to deliberately infect human lung fibroblasts (HLF) in vitro in order to study the molecular and cellular basis for the synergistic interactions with residual oil fly ash and its attendant metals such as Ni on host-cell production of immune-modulating cytokines such as IL-6. We propose 4 specific aims: 1) To establish and characterize the synergistic interaction of chemical stress (ROFA and Ni exposure) and microbial stress (M. fermentans infection) to stimulate the production of inflammatory and immune-modulating cytokines by HLF 2) To demonstrate that toll-like receptor-2 (TLR-2) specific stimuli (MALP-2) and Ni synergistically interact to produce inflammation and fibrosis within the lung in vivo; 3) To define the importance of Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) in mediating the synergistic interactions between metal-containing Ni and MALP-2; 4) To determine if Ni exposure can enhance activation of innate immunity by microbial components via modulation of the early signaling events of TLR-2 signal transduction. These studies will provide valuable insight into the mechanisms by which microorganisms like M. fermentans upregulate host-defense mechanisms within the lung and modulate the inflammatory response to environmental chemicals. The identification of microbial agents as determinants of host-cell response to chemical stress will necessitate that microbial ecology be taken into consideration in the assessment of risk posed by atmospheric pollutants such as ROFA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011986-02
Application #
7074068
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Mastin, Patrick
Project Start
2005-06-06
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$269,379
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Brant, Kelly A; Fabisiak, James P (2013) Role of hypoxia-inducible factor 1, ? subunit and cAMP-response element binding protein 1 in synergistic release of interleukin 8 by prostaglandin E2 and nickel in lung fibroblasts. Am J Respir Cell Mol Biol 49:105-13
Gao, Fei; Brant, Kelly A; Ward, Rachel M et al. (2010) Multiple protein kinase pathways mediate amplified IL-6 release by human lung fibroblasts co-exposed to nickel and TLR-2 agonist, MALP-2. Toxicol Appl Pharmacol 247:146-57
Brant, Kelly A; Fabisiak, James P (2009) Nickel and the microbial toxin, MALP-2, stimulate proangiogenic mediators from human lung fibroblasts via a HIF-1alpha and COX-2-mediated pathway. Toxicol Sci 107:227-37
Brant, Kelly A; Fabisiak, James P (2008) Nickel alterations of TLR2-dependent chemokine profiles in lung fibroblasts are mediated by COX-2. Am J Respir Cell Mol Biol 38:591-9
Shvedova, Anna A; Fabisiak, James P; Kisin, Elena R et al. (2008) Sequential exposure to carbon nanotubes and bacteria enhances pulmonary inflammation and infectivity. Am J Respir Cell Mol Biol 38:579-90
Fabisiak, James P; Gao, Fei; Thomson, Robyn G et al. (2006) Mycoplasma fermentans and TNF-beta interact to amplify immune-modulating cytokines in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 291:L781-93