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.
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.
| Mathews, Joel A; Krishnamoorthy, Nandini; Kasahara, David I et al. (2018) Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-Releasing Peptide. Am J Respir Cell Mol Biol 58:341-351 |
| Krishnamoorthy, Nandini; Douda, David N; Brüggemann, Thayse R et al. (2018) Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma. Sci Immunol 3: |
| Mathews, Joel A; Krishnamoorthy, Nandini; Kasahara, David Itiro et al. (2017) IL-33 Drives Augmented Responses to Ozone in Obese Mice. Environ Health Perspect 125:246-253 |
| Ricklefs, Isabell; Barkas, Ioanna; Duvall, Melody G et al. (2017) ALX receptor ligands define a biochemical endotype for severe asthma. JCI Insight 2: |
| Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356 |
| Duvall, Melody G; Barnig, Cindy; Cernadas, Manuela et al. (2017) Natural killer cell-mediated inflammation resolution is disabled in severe asthma. Sci Immunol 2: |
| Duvall, Melody G; Bruggemann, Thayse R; Levy, Bruce D (2017) Bronchoprotective mechanisms for specialized pro-resolving mediators in the resolution of lung inflammation. Mol Aspects Med 58:44-56 |
| Basil, Maria C; Levy, Bruce D (2016) Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol 16:51-67 |
| Colby, Jennifer K; Abdulnour, Raja-Elie E; Sham, Ho Pan et al. (2016) Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia. Am J Pathol 186:1801-1813 |
| Duvall, Melody G; Levy, Bruce D (2016) DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation. Eur J Pharmacol 785:144-155 |
Showing the most recent 10 out of 29 publications
