Organic dust exposure is an important occupational hazard for persons who work in swine confinement barns. Organic dust exposure to naive individuals results in an intense systemic and pulmonary inflammatory response that attenuates over time, suggestive of immunologic adaptation. However, despite evidence for adaptation to the exposure, one-third of all workers develop chronic lung disease. This important observation suggests that repeat organic dust exposure modulates the immune system response. Numerous studies have characterized the inflammatory response to a single organic dust exposure, but there have been few studies characterizing the response to repeat exposures. Utilizing a newly developed murine model, the investigators have demonstrated that mice adapt to repeat swine facility organic dust exposure, yet manifest evidence of lung tissue inflammation. This led them to explore the innate immune inflammatory response to repeat versus single organic dust exposure. In human monocytes, the investigators found that a unique inflammatory response occurs to repeat swine facility organic dust exposure as compared to a single exposure, which is independent of endotoxin. Repeat exposure to swine facility dust results in diminished tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1-beta, but persistently elevated IL-8 and IL-10 compared to a single dust challenge in human monocytes. Elevated IL-10 suppresses pro-inflammatory cytokines, but has also been associated with mucus metaplasia and lung tissue inflammation in mice. Preliminary data also suggest that the inflammatory response to organic dust may be mediated through protein kinase C (PKC) activity. Based on these novel observations, the investigators hypothesize that chronic innate immune inflammatory adaptation responses occur with repeat organic dust exposure. To test this hypothesis, they will perform experiments outlined in three specific aims.
In aim 1, the investigators will characterize and establish the inflammatory mediators involved with repeat versus single organic dust exposure in human monocytes.
In aim 2, they will determine the mechanisms of repeat versus single organic dust-induced inflammation focusing on the key role of PKC activation.
In aim 3, the investigators will determine the role of specific inflammatory mediators and PKC activation using an in vivo model of repeat versus single organic dust exposure in mice. Finally, the candidate is an adult allergist and immunologist with an interest in organic dust-induced diseases. She is a well-supported candidate with a long-standing interest in becoming a physician scientist who will benefit highly from a Clinical Scientist Development Award.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08ES015522-04
Application #
7825466
Study Section
Environmental Health Sciences Review Committee (EHS)
Program Officer
Shreffler, Carol K
Project Start
2007-05-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$191,474
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
Poole, Jill A; Gleason, Angela M; Bauer, Christopher et al. (2012) ?? T cells and a mixed Th1/Th17 response are important in organic dust-induced airway disease. Ann Allergy Asthma Immunol 109:266-273.e2
Poole, Jill A; Romberger, Debra J; Bauer, Chris et al. (2012) Protein kinase C epsilon is important in modulating organic-dust-induced airway inflammation. Exp Lung Res 38:383-95
Poole, Jill A; Gleason, Angela M; Bauer, Christopher et al. (2012) CD11c(+)/CD11b(+) cells are critical for organic dust-elicited murine lung inflammation. Am J Respir Cell Mol Biol 47:652-9
Wyatt, Todd A; Sisson, Joseph H; Allen-Gipson, Diane S et al. (2012) Co-exposure to cigarette smoke and alcohol decreases airway epithelial cell cilia beating in a protein kinase C?-dependent manner. Am J Pathol 181:431-40
Poole, Jill A; Romberger, Debra J (2012) Immunological and inflammatory responses to organic dust in agriculture. Curr Opin Allergy Clin Immunol 12:126-32
Poole, Jill A (2012) Farming-associated environmental exposures and effect on atopic diseases. Ann Allergy Asthma Immunol 109:93-8
Harting, Janel R; Gleason, Angela; Romberger, Debra J et al. (2012) Chronic obstructive pulmonary disease patients have greater systemic responsiveness to ex vivo stimulation with swine dust extract and its components versus healthy volunteers. J Toxicol Environ Health A 75:1456-70
Poole, Jill A; Wyatt, Todd A; Kielian, Tammy et al. (2011) Toll-like receptor 2 regulates organic dust-induced airway inflammation. Am J Respir Cell Mol Biol 45:711-9
Poole, Jill A; Kielian, Tammy; Wyatt, Todd A et al. (2011) Organic dust augments nucleotide-binding oligomerization domain expression via an NF-{kappa}B pathway to negatively regulate inflammatory responses. Am J Physiol Lung Cell Mol Physiol 301:L296-306
Slager, Rebecca E; Simpson, Sean L; Levan, Tricia D et al. (2010) Rhinitis associated with pesticide use among private pesticide applicators in the agricultural health study. J Toxicol Environ Health A 73:1382-93

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