The proposed experiments will test the hypothesis that allergic airway inflammation leads to the generation of specialized pro-resolving mediators that engage innate immune effector mechanisms, including innate lymphoid cells, to limit adaptive inflammation - a regulatory mechanism that is disrupted by viral infection in the setting of asthma exacerbation. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness during asthma exacerbations as the result of an over-abundance of pro-inflammatory stimuli, the severity and duration of an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Cysteinyl leukotrienes are well appreciated to play pro-phlogistic roles in asthma, but not all lipid mediators initiate inflammation. There are now several families of specialized pro-resolving mediators (SPM) that have been identified and characterized in acute inflammation. These protective mediators are enzymatically derived from essential fatty acids and serve as agonists at specific receptors to transduce cell type specific functional responses, including many that are relevant in asthma. With several drugs already developed to block leukotriene formation or action, the notion that select endogenous lipid-derived mediators are generated to promote resolution of asthmatic airway responses would turn conventional thinking on its head, and identify these natural pro-resolving mediators as novel templates for drug design. To test our hypothesis, we propose three specific aims to: Establish the time course for SPM biosynthesis in house dust mite-driven allergic airways responses;Determine innate immune mechanisms for SPM bioactions on innate lymphoid cells;and Examine the disruption of SPM formation and actions by viral infection. This proposal's specific aims are directed towards uncovering basic mechanisms that govern the resolution of allergic airway responses in health and disease.

Public Health Relevance

Asthma exacerbations are the most serious expression of the disease, and despite available therapies, asthma exacerbations remain common and lead to substantial morbidity. In this proposal, we are using self-limited models of asthma exacerbation to identify natural pro-resolving mediators and mechanisms. By understanding how the healthy lung restores homeostasis, we can better understand inflammatory diseases, such as asthma, and design novel rationale therapeutic strategies that quicken the resolution of asthma exacerbations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL122531-01
Application #
8672422
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2014-05-20
Project End
2018-04-30
Budget Start
2014-05-20
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$427,095
Indirect Cost
$159,595
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115