Organic dust exposure in the agricultural industry, particularly from large animal farming, results in significant airway disease including bronchitis, exacerbation of asthma, and obstructive lung disease. Initial exposure to organic dust induces an intense airway inflammatory response that wanes over time;however, persons repetitively exposed to these environments exhibit an increased risk of lung function decline, persistent inflammation and progressive respiratory impairment. We have demonstrated in our newly developed murine model that mice adapt to repetitive organic dust exposure, yet manifest evidence of chronic lung tissue inflammation and impaired alveolar macrophage function. We have also established in vitro that repetitive organic dust exposure profoundly impairs antigen presenting cell (APC) phenotype and function. As APCs function to recognize, respond, and clear inhaled agents/toxins while mediating adaptive immunity, a functionally impaired APC due to repetitive dust exposure would likely contribute to worsening respiratory disease. The mechanisms underlying these observations are not clear and could lead to the development of novel treatments to prevent and manage organic dust-induced airway disease in agriculture workers. The inherent complexity of the dust is a challenge in defining mechanisms of organic dust-induced inflammatory responses. One established inflammatory component in organic dusts is endotoxin;however, epidemiologic and laboratory-based studies have failed to link endotoxin exposure to disease manifestations. Our recent analysis has revealed a strong predominance of Gram-positive (rather than Gram-negative) bacteria and chemical analysis demonstrated a high concentration of muramic acid, a component of peptidoglycan (PGN) from the bacterial cell wall, in large animal farming environments. Our studies also support that non-endotoxin components, such as PGN, are driving the innate immune inflammatory responses to large animal farming dusts. Gram-positive PGN and its degradation products can act through several pattern-recognition receptors including cell surface Toll-like receptor 2 (TLR2) and the cytosolic nuclear oligomerization domain molecule (NOD2). Our preliminary data suggest that TLR2 and NOD2 are important signal transduction molecules key to the regulation of organic dust-induced inflammation. These novel observations led us to hypothesize that pattern recognition receptors responsible for recognizing Gram-positive peptidoglycan regulate the chronic inflammatory response to large animal organic dust exposure. To test this hypothesis we will perform experiments outlined in three specific aims: 1) determine the time course and reversibility of NOD2 expression by antigen presenting cells with organic dust exposure and the signaling pathways responsible for its expression;2) define the functional role of NOD2 and TLR2 in modulating APC response to activation following organic dust exposure in knock-out mice in vitro and in vivo;and 3) investigate whether mice deficient in either NOD2 or TLR2 exhibit altered susceptibility to organic dust exposure induced airway disease.

Public Health Relevance

The significance of this proposal lies in identifying mechanisms by which the Gram-positive microbial components present in organic dust mediate inflammation, which represents a paradigm shift from the current dogma focused on endotoxin-driven mechanisms. This project will help identify novel inflammatory targets that could lead to new prevention and treatment strategies of individuals subjected to repeated organic dust exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019325-03
Application #
8272649
Study Section
Special Emphasis Panel (ZES1-TN-J (R))
Program Officer
Nadadur, Srikanth
Project Start
2010-09-23
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$365,248
Indirect Cost
$119,290
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
Poole, Jill A; Anderson, Leigh; Gleason, Angela M et al. (2015) Pattern recognition scavenger receptor A/CD204 regulates airway inflammatory homeostasis following organic dust extract exposures. J Immunotoxicol 12:64-73
Bailey, Kl; Wyatt, Ta; Wells, Sm et al. (2014) Dimethylarginine dimethylaminohydrolase (DDAH) overexpression attenuates agricultural organic dust extract-induced inflammation. J Environ Immunol Toxicol 2:72-78
Boissy, Robert J; Romberger, Debra J; Roughead, William A et al. (2014) Shotgun pyrosequencing metagenomic analyses of dusts from swine confinement and grain facilities. PLoS One 9:e95578
Wells, Adam D; Poole, Jill A; Romberger, Debra J (2014) Influence of farming exposure on the development of asthma and asthma-like symptoms. Int Immunopharmacol 23:356-63
Wyatt, Todd A; Poole, Jill A; Nordgren, Tara M et al. (2014) cAMP-dependent protein kinase activation decreases cytokine release in bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 307:L643-51
Nordgren, Tara M; Wyatt, Todd A; Sweeter, Jenea et al. (2014) Motile cilia harbor serum response factor as a mechanism of environment sensing and injury response in the airway. Am J Physiol Lung Cell Mol Physiol 306:L829-39
Dusad, Anand; Thiele, Geoff M; Klassen, Lynell W et al. (2013) Organic dust, lipopolysaccharide, and peptidoglycan inhalant exposures result in bone loss/disease. Am J Respir Cell Mol Biol 49:829-36
Golden, Gregory A; Wyatt, Todd A; Romberger, Debra J et al. (2013) Vitamin D treatment modulates organic dust-induced cellular and airway inflammatory consequences. J Biochem Mol Toxicol 27:77-86
Oldenburg, Peter J; Poole, Jill A; Sisson, Joseph H (2012) Alcohol reduces airway hyperresponsiveness (AHR) and allergic airway inflammation in mice. Am J Physiol Lung Cell Mol Physiol 302:L308-15
Poole, Jill A; Romberger, Debra J (2012) Immunological and inflammatory responses to organic dust in agriculture. Curr Opin Allergy Clin Immunol 12:126-32

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