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. ? ? ?

National Institute of Health (NIH)
National Institute for Occupational Safety and Health (NIOSH)
Research Project (R01)
Project #
Application #
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Newhall, Jim
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Nordgren, Tara M; Bailey, Kristina L; Heires, Art J et al. (2018) Effects of Agricultural Organic Dusts on Human Lung-Resident Mesenchymal Stem (Stromal) Cell Function. Toxicol Sci 162:635-644
Chandra, Deepak; Poole, Jill A; Bailey, Kristina L et al. (2018) Dimethylarginine dimethylaminohydrolase (DDAH) overexpression enhances wound repair in airway epithelial cells exposed to agricultural organic dust. Inhal Toxicol 30:133-139
Nelson, Amy J; Roy, Shyamal K; Warren, Kristi et al. (2018) Sex differences impact the lung-bone inflammatory response to repetitive inhalant lipopolysaccharide exposures in mice. J Immunotoxicol 15:73-81
Nordgren, Tara M; Heires, Art J; Bailey, Kristina L et al. (2018) Docosahexaenoic acid enhances amphiregulin-mediated bronchial epithelial cell repair processes following organic dust exposure. Am J Physiol Lung Cell Mol Physiol 314:L421-L431
Warren, Kristi J; Wyatt, Todd A; Romberger, Debra J et al. (2017) Post-injury and resolution response to repetitive inhalation exposure to agricultural organic dust in mice. Safety (Basel) 3:
Wells, Adam; Romberger, Debra J; Thiele, Geoffrey M et al. (2017) Systemic IL-6 Effector Response in Mediating Systemic Bone Loss Following Inhalation of Organic Dust. J Interferon Cytokine Res 37:9-19
Weissenburger-Moser, Lisa; Meza, Jane; Yu, Fang et al. (2017) A principal factor analysis to characterize agricultural exposures among Nebraska veterans. J Expo Sci Environ Epidemiol 27:214-220
Wyatt, Todd A; Canady, Kerry; Heires, Art J et al. (2017) Alcohol Inhibits Organic Dust-induced ICAM-1 Expression on Bronchial Epithelial Cells. Safety (Basel) 3:
Schneberger, David; DeVasure, Jane M; Bailey, Kristina L et al. (2017) Effect of low-level CO2 on innate inflammatory protein response to organic dust from swine confinement barns. J Occup Med Toxicol 12:9
Gerald, Carresse L; Romberger, Debra J; DeVasure, Jane M et al. (2016) Alcohol Decreases Organic Dust-Stimulated Airway Epithelial TNF-Alpha Through a Nitric Oxide and Protein Kinase-Mediated Inhibition of TACE. Alcohol Clin Exp Res 40:273-83

Showing the most recent 10 out of 44 publications