Sulfur mustard (SM) and nitrogen mustard are high priority chemical threats that cause debilitating damage tothe respiratory system resulting in both acute and chronic effects. As this is the major cause of morbidity andmortality in exposed victims, it is essential to identify effective strategies to mitigate pulmonary toxicity causedby these vesicants. Our studies are focused on macrophages and inflammatory mediators as key to bothacute lung injury and fibrosis induced by vesicants.We discovered that following mustard exposure, distinct subset of macrophages with proinflammatory/cytotoxic activity (M1) and profibrotic (M2) activity sequentially appear in the lung. Our objective is to elucidatethe contribution of these macrophage subsets to mustard-induced lung injury and fibrosis, with the overall goalof identifying new targets for therapeutic intervention. This mechanistic research is essential as macrophagesare known to release numerous cytotoxic and profibrotic mediators; thus, targeting only one product ormacrophage subset is unlikely to be effective in completely mitigating vesicant-induced lung injury. Wehypothesize that M1 macrophages contribute to injury by generating cytotoxic oxidants and TNFα, which causelung damage and promote lipid oxidation; oxidized lipids and TNFα upregulate macrophage scavengerreceptors stimulating lipid uptake and the development of M2 macrophage foam cells, which play a key role infibrogenesis. To test this hypothesis plans are to (1) elucidate the origin of M1 and M2 inflammatorymacrophages responding to vesicant-induced lung injury and mechanisms mediating their accumulation in thelung; (2) Evaluate the role of oxidized lipids and M1 and M2 macrophages in foam cell formation and vesicant-induced fibrosis, and (3) Assess the contribution of TNFα to vesicant-induced acute lung injury and lungfibrosis. An innovative combination of strategies will be used for our studies including lineage tracking, thegeneration of chimeric mice, adoptive transfer and monocyte/ macrophage depletion. We will also work closelywith the Center's Pharmaceutics and Medicinal Chemistry Support Core to refine a microparticle lung drugdelivery system designed to specifically target profibotic M2 macrophages and with the Pharmacology andDrug Development Support Core to move one of our lead countermeasures for vesicant-induced lung injuryinto advanced drug development. Successful completion of our proposed studies will result in a more preciseunderstanding of the specific roles of macrophages in vesicant-induced toxicity, their origin, and mechanismsmediating their accumulation in the lung. This will have significant implications for the development of moreefficacious strategies for mitigating mustard-induced lung injury and fibrosis.
|Effective start/end date||4/6/15 → 9/22/16|
- National Institutes of Health (NIH)