Supplemental Figs. S1-S7

Most people with severe asthma have obesity. Metabolic dysfunction, often associated with obesity, is particularly associated with severe asthma. Mechanisms linking metabolic dysfunction with asthma, and whether improving metabolic function can affect asthma, are not known. The endocannabinoid system plays a significant role in metabolism; inhibition of cannabinoid receptor 1 (CB₁R) induces weight loss and improves serum lipid profiles. We used a CB₁R inverse agonist, INV-202, in a mouse model of obese asthma and investigated changes in weight, inflammation, airway reactivity, and surfactant lipids. Mice were fed low or high fat diets (LFD, HFD), and house dust mite extract (HDM) was delivered intranasally to induce allergic airway inflammation. Mice received INV-202 by oral gavage. Airway hyperresponsiveness was measured by flexivent and lung tissue cytokines were measured by ELISA. Leukocytes and lipids in the bronchoalveolar lavage fluid (BALF) were analyzed by flow cytometry and mass spectroscopy, respectively. LFD and HFD mice lost an average of 11% and 27% of their body weight, respectively. LFD mice had a 33% decrease in CCL20 in lung tissue and a 55% decrease in neutrophils in BALF. LFD and HFD mice had improvements in airway hyperresponsiveness, particularly as measured by reduced elastance. Phosphatidylglycerol in BALF increased with INV-202, which significantly correlated with compliance in LFD mice. This study supports a significant contribution of metabolic factors related to the endocannabinoid system in lung compliance and airway reactivity, in part through effects on surfactant lipid composition, and demonstrates the potential of CB₁R inverse agonists to treat obese asthma.

大多数重度哮喘患者伴有肥胖症。代谢功能障碍常与肥胖相关，且与重度哮喘的关联尤为密切。代谢功能障碍与哮喘之间的关联机制，以及改善代谢功能是否会影响哮喘病程，目前尚不清楚。内源性大麻素系统（endocannabinoid system）在代谢中发挥重要作用；抑制大麻素受体1（cannabinoid receptor 1, CB₁R）可诱导体重下降并改善血清脂质谱。本研究在肥胖哮喘小鼠模型中使用CB₁R反向激动剂INV-202，探究体重、炎症反应、气道反应性及表面活性物质脂质的变化。小鼠被喂食低脂饮食（low fat diet, LFD）或高脂饮食（high fat diet, HFD），并通过鼻腔给予屋尘螨提取物（house dust mite extract, HDM）以诱导过敏性气道炎症。小鼠通过灌胃方式接受INV-202给药。采用Flexivent系统测定气道高反应性，通过酶联免疫吸附试验（enzyme-linked immunosorbent assay, ELISA）检测肺组织细胞因子水平。支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）中的白细胞和脂质分别通过流式细胞术（flow cytometry）和质谱法（mass spectroscopy）分析。喂食LFD和HFD的小鼠平均体重分别下降11%和27%。喂食LFD的小鼠肺组织中CCL20水平下降33%，BALF中的中性粒细胞数量下降55%。喂食LFD和HFD的小鼠气道高反应性均有所改善，尤其表现为弹性降低。BALF中的磷脂酰甘油（phosphatidylglycerol）水平随INV-202给药升高，且与喂食LFD小鼠的肺顺应性显著相关。本研究表明，与内源性大麻素系统相关的代谢因素对肺顺应性和气道反应性具有重要影响，部分通过调控表面活性物质脂质组成实现；同时证实CB₁R反向激动剂具有治疗肥胖哮喘的潜力。