Cannabinoid-2 receptor signaling in vesicant induced lung injury

硫芥子气（SM）是一种最致命的化学战剂之一， 是现代社会的一大威胁暴露于SM及其单功能类似物2-氯乙基 乙基硫醚（CEES）诱导对肺的有害作用。氧化应激和失控 炎症被认为是SM对肺毒性的主要机制。目前 没有有效的医学对策来减轻起疱剂引起的肺损伤。 因此，有必要扩大我们对分子机制的理解， 有效措施，包括药物干预，以减轻炎症， SM诱导的氧化应激大麻素-2受体（CB 2 R），主要表达于 免疫细胞，已经显示出有希望的抗炎和抗损伤潜力， 不良精神影响我们的初步发现表明CEES显著降低- 通过药理学激活CB 2 R诱导急性肺损伤和免疫细胞浸润， 而CB 2 R基因缺失则加重肺损伤。此外，CB 2 R配体显示， CB 2 R具有明显的功能选择性，提示CB 2 R可作为开发抗肿瘤药物的良好靶点 措施CEES。鉴于这些有希望的迹象，该项目旨在进一步研究如何 CB 2 R激活可通过药理学激活减轻CEES诱导的急性肺损伤 和基因缺失的方法在以下具体目标：1）以确定在何种程度上， CB 2 R调节CEES诱导的急性肺损伤、炎症反应和氧化应激。 应力2)为了阐明CB 2 R在CEES诱导的肺损伤中保护作用的机制， 炎症反应和氧化应激。这些努力将揭示一种新的机制， CEES诱导的肺损伤中通过CB 2 R的内源性大麻素信号传导，并将有助于 抗疱剂诱导的肺的治疗剂的开发的翻译策略 损害

Sulfur mustard (SM), a vesicant that is one of the most lethal chemical warfare agents, remains as a great threat in modern times. Exposure to SM and its mono-functional analog 2-chloroethyl ethyl sulfide (CEES) induces deleterious effects on the lung. Oxidative stress and uncontrolled inflammation are considered as the major mechanisms of SM toxicity on the lung. Currently, there are no effective medical countermeasures to mitigate the vesicant induced lung damage. Therefore, it is essential to expand our understanding of the molecular mechanisms and to identify effective measures, including pharmacological interventions, to alleviate the inflammation and oxidative stress induced by SM. Cannabinoid-2 receptors (CB2R), expressed mainly in the immune cells, have shown promising anti-inflammatory and anti-injury potential without any adverse psychotic effects. Our preliminary findings indicated a significant reduction of CEES- induced acute lung injury and immune cell infiltration by pharmacological activation of CB2R, while the genetic deletion of CB2R worsened the lung injury. Moreover, CB2R ligands show marked functional selectivity, suggesting CB2R can be a good target for developing counter measures to CEES. Given these promising indications, this project aims to further investigate how CB2R activation attenuates CEES-induced acute lung injury, using pharmacological activation and genetic deletion approach in the following specific aims: 1) To determine the extent to which CB2R regulates the CEES-induced acute lung injury, inflammatory response, and oxidative stress. 2) To delineate the mechanism of the protective role of CB2R in CEES-induced lung injury, inflammatory response, and oxidative stress. These efforts will reveal a novel mechanism of endocannabinoid signaling through CB2R in CEES-induced lung injury and would assist in translational strategies for the development of therapeutic agent against vesicant-induced lung damage.