Pravastatin alleviates allergic airway inflammation in obesity-related asthma mouse model

<b>Background:</b> Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated. <b>Methods:</b> C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization and challenge. Pravastatin was administered intraperitoneally during the OVA treatment. Airway inflammation and airway hyper-responsiveness (AHR) were analyzed and lung tissues were examined. The changes in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were measured in the lung tissues. <b>Results:</b> HFD with OVA sensitization and challenge exacerbated eosinophilic and neutrophilic airway inflammation and increased AHR compared to lean asthma mice. The levels of cytokines examined in bronchoalveolar lavage fluid (BALF) revealed that the expressions of IL-4, 5, and 17 were elevated in the obese asthmatic group and decreased after pravastatin treatment, indicating that both the Th2 and Th17 pathways were stimulated by HFD-induced obesity and OVA challenge and suppressed by pravastatin treatment. Moreover, the serum leptin and adiponectin ratio was elevated only in obese asthmatic mice and decreased with pravastatin administration. Pravastatin successfully alleviated the airway inflammation of lung tissues and AHR in both obese and lean asthmatic mice, however, treatment with pravastatin had no effects on BALF cell counts and cytokines in lean asthma mice. In lung tissues, the phosphorylation of p38 MAPK was significantly decreased in lean as well as obese asthmatic mice. <b>Conclusions:</b> Pravastatin treatment in obese asthmatic mice suppressed allergic airway infiltration and AHR by inhibition of Th2 and Th17-associated signaling pathways, decreasing the leptin expression and downstream p38 MAPK signaling pathways. The effect on lean asthmatic mice was different, independent of airway cell counts and cytokines.

<b>研究背景：</b> 肥胖是与重度未控制哮喘相关的危险因素之一。目前尚无针对普伐他汀（pravastatin）在肥胖相关哮喘气道炎症中作用的相关研究评估。<b>研究方法：</b> 本研究采用高脂饮食（HFD）喂养C57BL/6小鼠以构建肥胖模型，设置是否联合卵清蛋白（OVA）致敏与激发的分组。在OVA干预期间，通过腹腔注射给予普伐他汀。随后检测气道炎症与气道高反应性（AHR），并对肺组织进行病理学检查。此外，检测肺组织中丝裂原活化蛋白激酶（MAPK）及磷脂酰肌醇3-激酶（PI3K）/Akt信号通路的活化变化。<b>研究结果：</b> 与瘦型哮喘小鼠相比，高脂饮食联合OVA致敏与激发可加重嗜酸性粒细胞性与中性粒细胞性气道炎症，并升高气道高反应性。对支气管肺泡灌洗液（BALF）中细胞因子的检测结果显示，肥胖哮喘组小鼠的白细胞介素4、5及17（IL-4、IL-5、IL-17）表达水平升高，普伐他汀干预后该水平显著降低，提示高脂饮食诱导的肥胖联合OVA激发可激活辅助性T细胞2（Th2）与辅助性T细胞17（Th17）通路，而普伐他汀可抑制该两条通路的活化。此外，仅在肥胖哮喘小鼠中可检测到血清瘦素与脂联素比值升高，普伐他汀干预后该比值显著下降。普伐他汀可有效减轻肥胖及瘦型哮喘小鼠的肺组织气道炎症与气道高反应性，但仅对肥胖哮喘小鼠的支气管肺泡灌洗液细胞计数及细胞因子水平产生影响，对瘦型哮喘小鼠无显著作用。经普伐他汀干预后，瘦型及肥胖哮喘小鼠肺组织内的p38丝裂原活化蛋白激酶（p38 MAPK）磷酸化水平均显著降低。<b>研究结论：</b> 普伐他汀可通过抑制Th2及Th17相关信号通路、下调瘦素表达及下游p38 MAPK信号通路，减轻肥胖哮喘小鼠的变应性气道浸润与气道高反应性。而普伐他汀对瘦型哮喘小鼠的作用机制不同，且与气道细胞计数及细胞因子水平无关。