Lung inflammatory models for the development of countermeasures against vesicants

我们研究的总体目标是阐明巨噬细胞和炎症介质在由水疱剂诱导的急性和慢性肺损伤中的作用，其长期目标是确定治疗干预的靶点。我们假设巨噬细胞在肺毒性中起双重作用。尽管最初经典活化的M1巨噬细胞通过释放过量的促炎/细胞毒性介质而导致急性组织损伤，但随后的释放 由过度活跃的M2巨噬细胞引起的促有丝分裂和纤维化介质的释放导致包括肺纤维化的慢性损伤。使用硫芥和氮芥作为模型发泡剂，计划确定M1和M2巨噬细胞亚群是否对发泡剂中毒的急性和长期后果有不同的贡献，以及是否通过改变它们的活性或介体释放来减轻毒性。与药物化学和制药核心合作，我们还计划 设计和评估由聚（乙二醇）水凝胶颗粒（“凝胶颗粒”或GP）组成的可注射肺递送系统，以靶向过度活跃的M1肺巨噬细胞和在发泡剂暴露后释放的细胞毒性/促炎介质。如果成功，我们的研究将提供一种策略，不仅用于治疗硫芥和氮芥诱导的肺毒性，而且用于治疗其他诱导肺损伤的化学威胁剂，包括氯气，光气和氨，以及其他与炎症相关的肺部病变。

The overall goal of our research is to elucidate the role of macrophages and inflammatory mediators in acute and chronic pulmonary injury induced by vesicants with the long-term objective of identifying targets for therapeutic intervention. We hypothesize that macrophages play a dual role in the pulmonary toxicity of vesicants. Whereas initially classically activated M1 macrophages contribute to acute tissue injury by releasing excessive quantities of proinflammatory/cytotoxic mediators, subsequent release of mitogenic and fibrogenic mediators by overactive M2 macrophages leads to chronic injury including pulmonary fibrosis. Using sulfur mustard and nitrogen mustard as model vesicants, plans are to determine if M1 and M2 macrophage subpopulations differentially contribute to the acute and long-term consequences of vesicant intoxication, and if pharmacologically modifying their activity or mediators they release mitigates toxicity. Working with the Medicinal Chemistry and Pharmaceutics Core, we also plan to engineer and evaluate an injectable lung delivery system consisting of poly(ethylene glycol) hydrogel particles ("gel particles" or GPs) to target hyperactive M1 lung macrophages and cytotoxic/proinflammatory mediators released following vesicant exposure. If successful, our studies will provide a strategy for treating not only sulfur mustard and nitrogen mustard-induced lung toxicity, but other chemical threat agents that induce pulmonary injury including chlorine, phosgene and ammonia, as well as other pulmonary pathologies associated with inflammation.