Cannabinoid-2 receptor signaling in vesicant induced lung injury

大麻素 2 受体信号传导在起泡剂引起的肺损伤中的作用

• 批准号: 10206949
• 负责人: Nagaraja Nagre
• 金额: $ 24.13万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-18 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206949
• 关键词: Acute; Acute Lung Injury; Address; Adult; Alkylating Agents; Anti-Inflammatory Agents; Attenuated; Biological; Bulla; CB2 knockout; CNR2 gene; Cells; Chemical Warfare Agents; Chronic; Coupling; DNA Damage; Data; Deacetylase; Deterioration; Development; Endocannabinoids; Erythroid; Event; Excision; Exhibits; Exposure to; Female; GTP-Binding Proteins; Gelatinase B; Genetic; Glutathione; Goals; Human; Human body; Immune; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knockout Mice; Lead; Life; Ligands; Lipid Peroxidation; Lung; Lung Inflammation; Measures; Mediating; Modernization; Molecular; Mus; Mustard Gas; Nuclear; Oxidative Stress; Pathologic; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Poison; Proteins; Pulmonary Inflammation; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Regulation; Research; Role; SIRT1 gene; Signal Transduction; Structure of parenchyma of lung; Study models; Sulfides; Testing; Therapeutic Agents; Therapeutic Effect; Time; Tissues; Toxic effect; Transcription Factor AP-1; Vesicants; analog; antioxidant enzyme; base; cytotoxic; effective therapy; endocannabinoid signaling; endogenous cannabinoid system; in vitro Model; lung injury; macrophage; male; medical countermeasure; monocyte; mortality; mouse model; novel; oxidation; receptor expression; receptor function; therapeutic development; therapeutically effective; translational approach; wound healing

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.

硫芥末（SM），一种囊泡，是最致命的化学战剂之一，仍然存在 作为现代的巨大威胁。暴露于SM及其单功能模拟2-氯乙基 乙基硫化物（CEES）诱导对肺的有害作用。氧化应激和不受控制的 炎症被认为是肺部SM毒性的主要机制。目前，那里 没有有效的医学对策来减轻囊泡诱导的肺损伤。 因此，必须扩展我们对分子机制的理解并确定 有效措施，包括药理干预措施，以减轻炎症和 SM诱导的氧化应激。大麻素-2受体（CB2R），主要在 免疫细胞已显示出有希望的抗炎和抗伤害潜力 不利的精神病作用。我们的初步发现表明CEES-大幅减少 通过CB2R的药理激活，诱导急性肺损伤和免疫细胞浸润， 而CB2R的遗传缺失使肺损伤恶化。此外，CB2R配体显示 明显的功能选择性，这表明CB2R可能是开发计数器的良好目标 采取措施。鉴于这些有希望的迹象，该项目旨在进一步研究 CB2R激活使用药理激活减轻了CEES诱导的急性肺损伤 以及以下特定目的中的遗传缺失方法：1）确定多大程度 CB2R调节CEES诱导的急性肺损伤，炎症反应和氧化性 压力。 2）描述CB2R在CEES引起的肺损伤中的保护作用的机制， 炎症反应和氧化应激。这些努力将揭示出一种新颖的机制 内源性大麻素通过CB2R在CEES引起的肺损伤中发出信号，将有助于 针对囊泡诱导的肺的治疗剂开发的翻译策略 损害。