Organic dust epithelial PKC activation & airway disease.
Romberger-DJ; Toews-M; West-W; Whatt-T; Meza-J; Parinandi-N
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-008539, 2010 Oct; :1-13
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 concentrated animal feeding operations (CAFOs). Persons exposed to hog CAFOs have airway inflammation and an increased incidence of COPD. Although many substances are present in hog barn dust that induce inflammation, 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 within the airways 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. Previously, 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. The objective of this proposal was 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 lysophosphatidic acid (LPA), an important lipid mediator, in modulating dust effects on PKC and inflammatory responses. We addressed our objective 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. The results of our studies support that several components of dusts found in hog CAFOs contribute to airway inflammation in workers in these facilities. Although endotoxin (from Gram-negative bacteria in the environment) is an important constituent of such dusts and a constituent of dusty environments that can be monitored, our data provides evidence that endotoxin alone is not the only important component of dusts in terms of respiratory disorders. We have observed that substances from Gram-positive bacteria (peptidoglycan) and proteases within the dust contribute substantially to airway epithelial inflammation. Better understanding of factors in dust that elicit airway inflammation is critical to enhancing the design of monitoring and prevention strategies for animal confinement facilities to protect the respiratory health of workers. We have created a mouse model with dust from hog confinement facilities (using intranasal exposure of dust extract) that demonstrates several features that are similar to respiratory disease seen in workers. This model shows a brisk initial inflammatory response to the dust extract, the development of some tolerance to the dust with repeated exposure, but significant lung inflammation with continued exposure. This animal model is important in ongoing work that allows us to study the mechanisms by which dust causes inflammation and to then test specific interventions to see if they improve the inflammation. Our data has provided new insights into the basic mechanisms by which dusts from confinement facilities cause inflammation in airways. We have demonstrated that dusts of swine confinement facilities activate specific isoforms of an important cell-signaling molecule protein kinase C (PKC) that regulates inflammatory mediator release of airway epithelial cells and inflammatory cell interactions with the epithelial cells. By defining the role of this important cell-signaling molecule in dust-induced airway inflammation, we can explore potential therapeutic interventions for airway disease focused on mediating the effect of dust on this pathway.
Organic-dusts; Dusts; Dust-inhalation; Inhalants; Pulmonary-system; Pulmonary-system-disorders; Pulmonary-disorders; Respiratory-system-disorders; Diseases; Exposure-levels; Animals; Farmers; Agriculture; Agricultural-industry; Molecular-biology; Cell-biology; Cellular-function; Cell-function; Bacterial-dusts; Bacteria; Workers; Work-environment
Debra J. Romberger, MD., University of Nebraska Medical Center, Dept. of Internal Medicine, Pulmonary, Critical Care, Sleep & Allergy Division, 985300 Nebraska Medical Center, Omaha, NE 68198-5300
Final Grant Report
NTIS Accession No.
Agriculture, Forestry and Fishing
National Institute for Occupational Safety and Health
University of Nebraska