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发泡剂引起的急性和慢性肺损伤中的作用，并确定治疗干预的长期目标。我们假设巨噬细胞在发泡剂的肺毒性中起双重作用。虽然最初经典激活的M1巨噬细胞通过释放过量的促炎/细胞毒介质而导致急性组织损伤，但随后的释放 过度活跃的M2巨噬细胞对促有丝分裂和纤维化介质的释放会导致包括肺纤维化在内的慢性损伤。使用硫芥末和氮芥末作为模型发泡剂，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，以及如果从药理上改变它们的活性或它们释放的介质可以减轻毒性。与药物化学和制药核心部门合作，我们还计划 设计和评估由聚乙二醇水凝胶颗粒组成的可注射肺给药系统(

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 (