Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and an estimated 15% of COPD cases are related to occupational exposures. In agricultural workers, organic dust exposures lead to damaging acute and chronic airway inflammation, and existing therapeutics do not adequately treat the resulting airway disease. Thus, novel preventative or treatment schemes are vitally needed to combat the deleterious inflammatory effects of these exposures. The health benefits of diets high in omega-3 fatty acids (?-3 FA) are well recognized, but incompletely understood. Recent studies reveal certain ?-3 FA derivatives attenuate and resolve inflammation. These pro-resolving mediators (PRM) may be key to the beneficial effects of ?-3 FA. Harnessing the anti-inflammatory and pro-resolving properties of PRM in preventative and treatment regimens could revolutionize the way we combat inflammatory disease processes. However, the potential for PRM in treating organic dust-related airway disease, as well as their effects on key airway inflammation initiators, the bronchial epithelial cells (BECs), have not yet been studied. Therefore, the objective for the proposed research is to determine the utility of a PRM, maresin-1 (MaR1), at limiting the inflammatory effects of organic dust exposures. It is hypothesized that MaR1 will reduce airway inflammation and increase the anti-inflammatory and pro-resolving actions of BECs during organic dust exposures. To test this hypothesis, two specific aims are proposed.
Aim 1 will focus on delineating the effects of MaR1 on organic dust-induced airway inflammation in a preclinical murine model of single and repetitive exposures.
Aim 2 will focus on establishing how MaR1 decreases the pro-inflammatory responses of BECs to organic dust by (a) determining what pro-inflammatory responses in dust extract-stimulated BECs are modified by MaR1, and (b) defining the mechanisms of MaR1-induced changes in dust extract-treated BECs. Taken together, the results of these aims are expected to have important positive impacts; they will demonstrate the utility of MaR1 in treating organic dust-induced airway disease, and expose the potential for PRM as primary or adjunct therapies in inflammatory airway diseases. These experiments are therefore of great translational significance, potentially transforming the way acute and chronic inflammatory airway diseases are prevented and treated.

Public Health Relevance

The proposed studies are relevant to public health because they will demonstrate how dietary omega-3 fatty acid-derived lipid mediators like maresin-1 can be used in treating and preventing airway inflammation and disease caused by agricultural-related dust exposures. These experiments will lay the foundation for testing these lipid mediators for their utility in other environmental exposure-related airway diseases, including those caused by tobacco smoke, diesel exhaust, and other air pollutants. This project is relevant to the mission of NIEHS because the expected results will advance efforts in promoting healthier lives by potentially transforming how environmental exposure-related airway diseases are prevented and treated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES022913-02
Application #
8803208
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Nadadur, Srikanth
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
2
Fiscal Year
2015
Total Cost
$56,042
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
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Romberger, Debra J; Heires, Art J; Nordgren, Tara M et al. (2016) ?2-Adrenergic agonists attenuate organic dust-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 311:L101-10
Nordgren, Tara M; Bailey, Kristina L (2016) Pulmonary health effects of agriculture. Curr Opin Pulm Med 22:144-9
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
Nordgren, Tara M; Bauer, Christopher D; Heires, Art J et al. (2015) Maresin-1 reduces airway inflammation associated with acute and repetitive exposures to organic dust. Transl Res 166:57-69
Nordgren, Tara M; Friemel, Taylor D; Heires, Art J et al. (2014) The omega-3 fatty acid docosahexaenoic acid attenuates organic dust-induced airway inflammation. Nutrients 6:5434-52
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Nordgren, Tara M; Heires, Art J; Wyatt, Todd A et al. (2013) Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust. Respir Res 14:51