Contribution of mast cells to nitrogen mustard pulmonary toxicity

摘要 肥大细胞是一种先天性免疫细胞，在粘膜表面以高丰度发现， 在外部环境中，它们作为免疫哨兵发挥主要作用，以检测损伤和侮辱。硫 芥子气（SM）是一种双功能烷化剂，已被用作化学战剂和暴露 导致严重的肺、眼和皮肤毒性。吸入SM会导致严重的肺损伤 包括气道损伤、组织重塑、大量免疫细胞募集、水肿等。 SM的毒性归因于其烷基化功能和DNA损伤，然而，这并不能解释SM的毒性。 观察到大量的炎症反应，也不知道这些炎症反应是如何引起的， 肺。我们假设SM激活肥大细胞是肥大细胞募集和增殖的起始步骤， 肺部的免疫反应。为了验证这一假设，我们将野生型或肥大细胞缺陷小鼠暴露于 氮芥（NM）（SM的替代物）以确定包括组织损伤的肺反应， 炎症和纤维化的发展。此外，我们将利用小鼠骨髓来源的肥大细胞， 研究NM导致肥大细胞活化的机制。具体来说，我们将调查NM是否 引起肥大细胞脱粒、脂质介质产生和/或细胞因子产生。总的来说，我们的目标是 确立肥大细胞在调节NM的肺毒性中的作用，从而提供一种新的治疗方法， 预防和/或治疗这些化学战剂影响的目标。初步数据 从这份补充材料中产生的信息将作为U 01向反法计划申请的基础 专注于SM毒性中的治疗靶向肥大细胞。

ABSTRACT 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.