抑制内源性大麻素代谢科减轻豚鼠卵蛋白诱导过敏性气道炎症及气道高反应
2022/09/20
摘要
背景：内源性大麻素是在许多哺乳动物组织中内源性合成的具有生物活性的大麻素相关物质。主要通过两种酶进行降解，即脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）。既往研究显示，内源性大麻素可影响炎症过程和气道反应性的调节。本研究旨在研究了FAAH 和 MAGL 抑制剂治疗对豚鼠实验性过敏性气道炎症的影响。
方法：用卵蛋白致敏和激发豚鼠以诱导建立过敏性哮喘模型。进而评估 FAAH 抑制剂 URB597、MAGL 抑制剂 JZL184 和双重（FAAH/MAGL）抑制剂 JZL195 对气道炎症和高反应性的影响。
结果：卵蛋白激发可加强气道反应性，并提高血清中 IgE、IL-4 和IL-13水平，同时提高支气管肺泡灌洗液（BAL）中嗜酸性粒细胞的百分比。此外，抑制 FAAH 或 MAGL 酶会导致内源性大麻素水平升高。 FAAH 酶的选择性抑制可抑制各项炎症指标（如细胞因子产生和炎症细胞浸润），但对气道高反应性的影响可忽略不计。然而，MAGL 酶的抑制或 FAAH 和 MAGL 酶的双重抑制倾向于减轻肺部炎症和气道高反应性。
结论：我们之前已经证明，FAAH 或 MAGL 可抑制调节气道中的内源性大麻素水平可用于预防急性肺部炎症。本研究的结果进一步表明，FAAH 和 MAGL 抑制剂也有望成为过敏性哮喘中支气管高反应性和气道炎症的治疗策略。
Endocannabinoid metabolism inhibition ameliorates ovalbumin-induced allergic airway inflammation and hyperreactivity in Guinea pigs.
Abohalaka R, Karaman Y, Recber T, Onder SC, Nemutlu E, Bozkurt TE.
Abstract
BACKGROUND:Endocannabinoids are biologically active cannabinoid-related substances endogenously synthesized in many mammalian tissues. Mainly two enzymes carry out their degradation; Fatty Acid Amide Hydrolase (FAAH) and Monoacylglycerol Lipase (MAGL). Endocannabinoids are shown to affect the modulation of inflammatory processes and airway responsiveness. In the present study, we investigated the effects of FAAH and MAGL inhibitor treatments in experimental allergic airway inflammation in guinea pigs.
METHODS:Guinea pigs were sensitized and challenged by ovalbumin to induce an allergic asthma model. Then, the effects of FAAH inhibitor URB597, MAGL inhibitor JZL184, and dual (FAAH/MAGL) inhibitor JZL195 on airway inflammation and hyperreactivity were evaluated.
RESULTS:of eosinophils in bronchoalveolar lavage (BAL). In addition, inhibition of FAAH or MAGL enzymes leads to an increase in endocannabinoid levels. The selective inhibition of the FAAH enzyme prevented inflammation indicators such as cytokine production and inflammatory cell infiltration but had a negligible effect on airway hyperreactivity. However, the inhibition of the MAGL enzyme or dual inhibition of both FAAH and MAGL enzymes tent to moderate both pulmonary inflammation and airway hyperreactivity.
CONCLUSIONS:We have previously demonstrated that modulation of endocannabinoid levels in the airways by FAAH or MAGL inhibition can be useful in preventing acute lung inflammation. The results of the present study further suggest that FAAH and MAGL inhibitor treatment can also be a promising strategy for bronchial hyperreactivity and airway inflammation in allergic asthma.
背景：内源性大麻素是在许多哺乳动物组织中内源性合成的具有生物活性的大麻素相关物质。主要通过两种酶进行降解，即脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）。既往研究显示，内源性大麻素可影响炎症过程和气道反应性的调节。本研究旨在研究了FAAH 和 MAGL 抑制剂治疗对豚鼠实验性过敏性气道炎症的影响。
方法：用卵蛋白致敏和激发豚鼠以诱导建立过敏性哮喘模型。进而评估 FAAH 抑制剂 URB597、MAGL 抑制剂 JZL184 和双重（FAAH/MAGL）抑制剂 JZL195 对气道炎症和高反应性的影响。
结果：卵蛋白激发可加强气道反应性，并提高血清中 IgE、IL-4 和IL-13水平，同时提高支气管肺泡灌洗液（BAL）中嗜酸性粒细胞的百分比。此外，抑制 FAAH 或 MAGL 酶会导致内源性大麻素水平升高。 FAAH 酶的选择性抑制可抑制各项炎症指标（如细胞因子产生和炎症细胞浸润），但对气道高反应性的影响可忽略不计。然而，MAGL 酶的抑制或 FAAH 和 MAGL 酶的双重抑制倾向于减轻肺部炎症和气道高反应性。
结论：我们之前已经证明，FAAH 或 MAGL 可抑制调节气道中的内源性大麻素水平可用于预防急性肺部炎症。本研究的结果进一步表明，FAAH 和 MAGL 抑制剂也有望成为过敏性哮喘中支气管高反应性和气道炎症的治疗策略。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Life Sci. 2022 Oct 1;306:120808. doi: 10.1016/j.lfs.2022.120808.)
(Life Sci. 2022 Oct 1;306:120808. doi: 10.1016/j.lfs.2022.120808.)
Endocannabinoid metabolism inhibition ameliorates ovalbumin-induced allergic airway inflammation and hyperreactivity in Guinea pigs.
Abohalaka R, Karaman Y, Recber T, Onder SC, Nemutlu E, Bozkurt TE.
Abstract
BACKGROUND:Endocannabinoids are biologically active cannabinoid-related substances endogenously synthesized in many mammalian tissues. Mainly two enzymes carry out their degradation; Fatty Acid Amide Hydrolase (FAAH) and Monoacylglycerol Lipase (MAGL). Endocannabinoids are shown to affect the modulation of inflammatory processes and airway responsiveness. In the present study, we investigated the effects of FAAH and MAGL inhibitor treatments in experimental allergic airway inflammation in guinea pigs.
METHODS:Guinea pigs were sensitized and challenged by ovalbumin to induce an allergic asthma model. Then, the effects of FAAH inhibitor URB597, MAGL inhibitor JZL184, and dual (FAAH/MAGL) inhibitor JZL195 on airway inflammation and hyperreactivity were evaluated.
RESULTS:of eosinophils in bronchoalveolar lavage (BAL). In addition, inhibition of FAAH or MAGL enzymes leads to an increase in endocannabinoid levels. The selective inhibition of the FAAH enzyme prevented inflammation indicators such as cytokine production and inflammatory cell infiltration but had a negligible effect on airway hyperreactivity. However, the inhibition of the MAGL enzyme or dual inhibition of both FAAH and MAGL enzymes tent to moderate both pulmonary inflammation and airway hyperreactivity.
CONCLUSIONS:We have previously demonstrated that modulation of endocannabinoid levels in the airways by FAAH or MAGL inhibition can be useful in preventing acute lung inflammation. The results of the present study further suggest that FAAH and MAGL inhibitor treatment can also be a promising strategy for bronchial hyperreactivity and airway inflammation in allergic asthma.
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