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.
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.
|Romberger, Debra J; Heires, Art J; Nordgren, Tara M et al. (2016) Î²2-Adrenergic agonists attenuate organic dust-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 311:L101-10|
|Warren, Kristi J; Sweeter, Jenea M; Pavlik, Jacqueline A et al. (2016) Sex differences in activation of lung-related type 2 innate lymphoid cells in experimental asthma. Ann Allergy Asthma Immunol :|
|Wunschel, Javen; Poole, Jill A (2016) Occupational agriculture organic dust exposure and its relationship to asthma and airway inflammation in adults. J Asthma 53:471-7|
|Staab, Elizabeth; Thiele, Geoffrey M; Clarey, Dillon et al. (2016) Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss. PLoS One 11:e0158735|
|Warren, Kristi J; Simet, Samantha M; Pavlik, Jacqueline A et al. (2016) RSV-specific anti-viral immunity is disrupted by chronic ethanol consumption. Alcohol 55:35-42|
|Dusad, Anand; Thiele, Geoffrey M; Klassen, Lynell W et al. (2015) Vitamin D supplementation protects against bone loss following inhalant organic dust and lipopolysaccharide exposures in mice. Immunol Res 62:46-59|
|Romberger, Debra J; Heires, Art J; Nordgren, Tara M et al. (2015) Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation. Am J Physiol Lung Cell Mol Physiol 309:L388-99|
|Hofmann, Jonathan N; Hoppin, Jane A; Lynch, Charles F et al. (2015) Farm characteristics, allergy symptoms, and risk of non-hodgkin lymphoid neoplasms in the agricultural health study. Cancer Epidemiol Biomarkers Prev 24:587-94|
|Poole, Jill A; Romberger, Debra J; Wyatt, Todd A et al. (2015) Age Impacts Pulmonary Inflammation and Systemic Bone Response to Inhaled Organic Dust Exposure. J Toxicol Environ Health A 78:1201-16|
|Hawley, Brie; Schaeffer, Joshua; Poole, Jill A et al. (2015) Differential response of human nasal and bronchial epithelial cells upon exposure to size-fractionated dairy dust. J Toxicol Environ Health A 78:583-94|
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