Exposure to organic dusts is a cause of airway disease, including chronic obstructive pulmonary disease (COPD). As many as 20% of COPD cases are attributed to occupational exposures. In rural areas, an important source of dust exposure occurs in hog confinement barns. Persons exposed to hog barns have airway inflammation and an increased incidence of COPD. Although many substances are present in hog barn dust that induces inflammation including endotoxins, actual mechanisms leading to COPD are not well defined. Understanding mechanisms of hog barn dust-induced airway disease is relevant in developing both targeted treatment and prevention strategies. Epithelial cells respond to inhaled agents with the release of cytokines that recruit and activate inflammatory cells and expression of molecules that serve as receptors and ligands for interactions with other cells. We observed that hog barn dust extract (HDE) augments human airway epithelial protein kinase C (PKC) activation, resulting in IL-8 and IL-6 release and increased ICAM-1 expression, mediating inflammatory cell adhesion to airway epithelium in vitro. Using an intranasal exposure to HDE in mice, we observed an increase in airway epithelial PKC activation and inflammatory responses in vivo. We recently observed that epithelial cell exposure to HDE results in an increase of the lipid mediator lysophosphatidic acid (LPA). Treatment with phospholipase B to inactivate LPA inhibits HDE-stimulated IL-6 and IL-8 release. The role of LPA induced by hog barn dust in directing airway inflammation is not known. The objective of this proposal is to define mechanisms by which hog barn dust activates epithelial cell PKC and the role of PKC in airway inflammation associated with chronic bronchitis occurring in confinement facility workers and to determine the role of hog barn dust-related LPA, an important lipid mediator, in modulating dust effects on PKC and inflammatory responses. We will address our hypothesis with these specific aims: 1) Determine the biochemical nature and specific identity of factor(s) in HDE that activate epithelial cell PKC and identify the specific PKC isoenzymes activated by HDE and these factors. 2) Establish how HDE-associated lysophosphatidic acid (LPA) modulates HDE-induced epithelial cell PKC activity and IL-8/IL-6 release. 3) Identify mechanisms by which HDE augmentation of epithelial cell PKC In vitro mediates recruitment and adhesion of inflammatory cells to airway epithelium in vitro. 4) Determine how HDE modulates airway epithelial PKC activation and inflammatory responses in vivo utilizing an animal model of exposure, including testing the potential role of LPA. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute for Occupational Safety and Health (NIOSH)
Type
Research Project (R01)
Project #
5R01OH008539-02
Application #
7269299
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Robison, William
Project Start
2006-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$340,000
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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