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.
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.
|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|