Mast cells are an innate immune cell found in high abundance at mucosal surfaces that interface with the external environment where they play a major role as an immune sentinel to detect injury and insult. Sulfur mustard (SM), a bi-functional alkylating agent, has been used as a chemical warfare agent and exposure causes severe pulmonary, ocular and dermal toxicity. SM causes severe pulmonary damage upon inhalation including damage to airways, tissue remodeling, massive immune cell recruitment, edema, etc. Much of the toxicity to SM is attributed to its alkylating function and DNA damage, however, this does not explain the massive inflammatory response observed nor is it known how these inflammatory responses are elicited in the lung. We hypothesize that activation of mast cells by SM is an initiating step in recruitment and propagation of immune responses in the lung. To test this hypothesis, we will expose wild-type or mast cell deficient mice to nitrogen mustard (NM) (a surrogate for SM) to determine pulmonary responses including tissue damage, inflammation and development of fibrosis. In addition, we will utilize mouse bone marrow-derived mast cells to examine mechanisms by which NM leads to mast cell activation. Specifically, we will investigate whether NM causes mast cell degranulation, lipid mediator production and/or cytokine production. Overall, our goal is to establish a role for mast cells in regulating the pulmonary toxicity to NM thereby providing a novel therapeutic target for prevention and/or treatment of the effects of these chemical warfare agents. The preliminary data generated from this supplement will be used as the basis for a U01 application to the CounterAct program focused on therapeutically targeting mast cells in SM toxicity.
Our preliminary data suggests a role for mast cells in the pulmonary toxicity to nitrogen mustard, an alkylating agent used for chemical warfare. In this supplement award, we will investigate the contribution of mast cells to pulmonary inflammation and tissue remodeling following exposure to nitrogen mustard using a mast cell deficient mouse model. In addition, we will examine mechanisms by which nitrogen mustard activates masts cell in vitro.
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