The contribution of the endocannabinoid system to both physiology and pathological processes in the respiratory system makes it a promising target for inflammatory airway diseases. Previously, we have shown that increasing the tissue endocannabinoid levels by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors can prevent airway inflammation and hyperreactivity. In this study, the changes in the levels of major metabolites of endocannabinoids by systemic and local FAAH or MAGL inhibitor treatments were evaluated. Mice were treated with either the FAAH inhibitor URB597 or the MAGL inhibitor JZL184 by local (intranasal) or systemic (intraperitoneal) application. Bronchoalveolar lavage (BAL) fluids and lungs were isolated afterward in order to perform histopathological and metabolomic analyses. There were no significant histopathological changes in the lungs and neutrophil, and macrophage and lymphocyte numbers in BAL fluid were not altered after local and systemic treatments. However, GC–MS-based metabolomics profile allowed us to identify 102 metabolites in lung samples, among which levels of 75 metabolites were significantly different from the control. The metabolites whose levels were changed by treatments were mostly related to the endocannabinoid system and energy metabolism. Therefore, these changes may contribute to the anti-inflammatory effects of URB597 and JZL184 treatments in mice.

中文翻译：

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全身和局部脂肪酸酰胺水解酶和单酰基甘油脂肪酶抑制剂治疗对肺代谢组学特征的影响

内源性大麻素系统对呼吸系统生理和病理过程的贡献使其成为炎症性气道疾病的有希望的靶点。以前，我们已经表明，通过脂肪酸酰胺水解酶 (FAAH) 和单酰基甘油脂肪酶 (MAGL) 抑制剂增加组织内源性大麻素水平可以预防气道炎症和高反应性。在这项研究中，评估了全身和局部 FAAH 或 MAGL 抑制剂治疗对内源性大麻素主要代谢物水平的变化。通过局部（鼻内）或全身（腹膜内）应用，用 FAAH 抑制剂 URB597 或 MAGL 抑制剂 JZL184 治疗小鼠。之后分离支气管肺泡灌洗 (BAL) 液和肺以进行组织病理学和代谢组学分析。在局部和全身治疗后，肺和中性粒细胞没有显着的组织病理学变化，BAL液中的巨噬细胞和淋巴细胞数量没有改变。然而，基于 GC-MS 的代谢组学分析使我们能够鉴定肺样本中的 102 种代谢物，其中 75 种代谢物的水平与对照显着不同。水平因治疗而改变的代谢物主要与内源性大麻素系统和能量代谢有关。因此，这些变化可能有助于 URB597 和 JZL184 治疗小鼠的抗炎作用。基于 GC-MS 的代谢组学分析使我们能够鉴定肺样本中的 102 种代谢物，其中 75 种代谢物的水平与对照显着不同。水平因治疗而改变的代谢物主要与内源性大麻素系统和能量代谢有关。因此，这些变化可能有助于 URB597 和 JZL184 治疗小鼠的抗炎作用。基于 GC-MS 的代谢组学分析使我们能够鉴定肺样本中的 102 种代谢物，其中 75 种代谢物的水平与对照显着不同。水平因治疗而改变的代谢物主要与内源性大麻素系统和能量代谢有关。因此，这些变化可能有助于 URB597 和 JZL184 治疗小鼠的抗炎作用。