Cannabinoid-2 receptor signaling in vesicant induced lung injury

硫磺芥末(SM)，一种发泡剂，是最致命的化学战剂之一，仍然存在 在现代是一个巨大的威胁。暴露于SM及其单功能类似物2-氯乙基 乙硫醚(CEES)对肺部有不良影响。氧化应激与失控 炎症被认为是丹参对肺毒性的主要机制。目前，有 目前尚无有效的药物治疗方法来减轻发泡剂所致的肺损伤。 因此，有必要扩大我们对分子机制的理解，并对其进行鉴定 有效措施，包括药物干预，以减轻炎症和 SM诱导的氧化应激。大麻素2受体(CB2R)，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，而没有任何 对精神有不良影响。我们的初步调查结果表明，CEES显著减少- CB2R药理激活所致急性肺损伤和免疫细胞浸润 而CB2R基因缺失加重了肺损伤。此外，CB2R配体显示 显著的功能选择性，表明CB2R可以成为开发计数器的良好目标 针对CEES的措施。鉴于这些有希望的迹象，该项目旨在进一步调查 CB2R激活通过药理激活减轻CEES诱导的急性肺损伤 和基因缺失的方法有以下具体目的：1)确定基因缺失的程度 CB2R对CEES诱导的急性肺损伤、炎症反应和氧化的调节作用 压力。2)探讨CB2R对CEES诱导的肺损伤的保护作用机制。 炎症反应和氧化应激。这些努力将揭示一种新的机制 CB2R介导的内源性大麻素信号转导在CEES诱导的肺损伤中的作用 泡剂肺治疗药物开发的翻译策略 损坏。

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.