Cannabinoids and the endocannabinoid system significantly contributes to the airway inflammation. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are two main enzymes responsible for the metabolism of the endocannabinoids anandamide (AEA) and 2-arachydonoyl glycerol (2-AG), respectively. In the present study, we aimed to investigate the effects of local and systemic FAAH and MAGL inhibitor treatments in experimental airway inflammation and tracheal hyperreactivity in mice.

Airway inflammation was induced by intranasal (i.n.) lipopolysaccharide (LPS) application (60 μl; 0,1 mg/ml in PBS) to mice and the control group received PBS. Systemic (intraperitoneal (i.p.)) or local (i.n.) FAAH inhibitor URB597 and MAGL inhibitor JZL184 treatments were administered 1h before LPS/PBS application. Fourty 8 h after LPS/PBS application, tracheas were removed to assess airway reactivity, and the lungs and bronchoalveolar lavage (BAL) fluids were isolated for histopathological evaluation, cytokine and endocannabinoid measurements.

LPS application lead to an increase in 5-hydroxytryptamine (5-HT) contractions in isolated tracheal rings while carbachol contractions remained unchanged. The increased 5-HT contractions were prevented by both systemic and local URB597 and JZL184 treatments. Systemic treatment with URB597 and JZL184, and local treatment with JZL184 reduced peribronchial and paranchymal inflammation in the LPS group while i.n. application of URB597 worsened the inflammation in the lungs. Systemic URB597 treatment increased lung AEA level whereas it had no effect on 2-AG level. However, JZL184 treatment increased 2-AG level by either systemic or local application, and also elevated AEA level. Inflammation-induced increase in neutrophil numbers was only prevented by systemic URB597 treatment. However, both URB597 and JZL184 treatments abolished the increased TNF-α level either they are administered systemically or locally.

These results indicate that FAAH and MAGL inhibition may have a protective effect in airway inflammation and airway hyperreactivity, and therefore their therapeutic potential for airway diseases should be further investigated.

大麻素和内源性大麻素系统显着促进气道炎症。脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂酶（MAGL）是分别负责内源性大麻素anandamide（AEA）和2-arachydonoyl甘油（2-AG）代谢的两个主要酶。在本研究中，我们旨在研究局部和全身性FAAH和MAGL抑制剂治疗对小鼠实验性气道炎症和气管反应过度的影响。

通过鼻内脂多糖（LPS）（60μl； 0.1 mg / ml于PBS中）对小鼠的应用诱发气道炎症，对照组接受PBS。在应用LPS / PBS之前1小时，系统性（腹膜内（ip））或局部（局部）FAAH抑制剂URB597和MAGL抑制剂JZL184治疗。施用LPS / PBS后48小时，取出气管以评估气道反应性，并分离肺和支气管肺泡灌洗液（BAL）以进行组织病理学评估，细胞因子和内源性大麻素测量。

LPS的使用导致孤立的气管环中5-羟色胺（5-HT）收缩增加，而卡巴胆碱的收缩保持不变。全身和局部URB597和JZL184治疗均可以防止5-HT收缩增加。在LPS组中，使用URB597和JZL184进行全身治疗，以及使用JZL184进行局部治疗，可减少支气管周围和支气管旁的炎症，而在应用URB597时，可使肺部的炎症恶化。全身性URB597治疗可增加肺部AEA水平，而对2-AG水平无影响。但是，JZL184治疗可通过全身或局部应用增加2-AG的水平，并提高AEA的水平。炎症引起的中性粒细胞数量的增加只能通过全身性URB597治疗来预防。然而，

这些结果表明FAAH和MAGL抑制可能对气道炎症和气道高反应性具有保护作用，因此应进一步研究其对气道疾病的治疗潜力。