Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, Liaoning Province, China; Department of Pediatrics, The Second Hospital of Dalian Medical University, No. 467, Zhongshan Road, Shahekou District, Dalian 116021, Liaoning Province, China.
Department of Pediatrics, Xi'an Children's Hospital, No. 69, Xi Ju Yuan Xiang, Lianhu District, Xi'an 710002, Shanxi Province, China.
Int Immunopharmacol. 2023 Jun;119:110149. doi: 10.1016/j.intimp.2023.110149. Epub 2023 Apr 12.
Obese asthma is a form of refractory asthma with inflammation as the underlying mechanism. The specific mechanism of action of anti-inflammatory growth differentiation factor 15 (GDF15) in obese asthma is unclear. The purpose of this study was to explore the effect of GDF15 on cell pyroptosis in obese asthma and to determine its mechanism of airway protection. Male C57BL6/J mice were fed with a high-fat diet, sensitized, and challenged with ovalbumin. Recombinant human (rh)GDF15 was administered 1 h before the challenge. GDF15 treatment significantly reduced airway inflammatory cell infiltration, mucus hypersecretion and airway resistant, and decreased cell counts and inflammatory factors in bronchoalveolar lavage fluid. Serum inflammatory factors decreased, and the increased levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and gasdermin-D (GSDMD-N) in obese asthmatic mice were inhibited. Furthermore, the suppressed phosphoinositide 3-kinase (PI3K)/AKT signal pathway was activated after rhGDF15 treatment. The same result was obtained by overexpression of GDF15 in human bronchial epithelial cells induced by lipopolysaccharide (LPS) in vitro, and the effect of GDF15 was reversed after the application of a PI3K pathway inhibitor. Thus, GDF15 could protect the airway by inhibiting cell pyroptosis in obese asthmatic mice through the PI3K/AKT signaling pathway.
肥胖型哮喘是一种以炎症为潜在机制的难治性哮喘。抗炎生长分化因子 15（GDF15）在肥胖型哮喘中作用的确切机制尚不清楚。本研究旨在探讨 GDF15 对肥胖型哮喘细胞焦亡的影响，并确定其气道保护作用机制。雄性 C57BL6/J 小鼠给予高脂饮食，致敏并用卵清蛋白激发。在激发前 1 小时给予重组人（rh）GDF15。GDF15 治疗可显著减轻气道炎症细胞浸润、黏液高分泌和气道阻力，减少支气管肺泡灌洗液中的细胞计数和炎症因子。血清炎症因子减少，肥胖型哮喘小鼠中 NLR 家族含pyrin 结构域蛋白 3（NLRP3）、半胱氨酸天冬氨酸蛋白酶-1（caspase-1）、凋亡相关斑点样蛋白（ASC）和含gasdermin-D（GSDMD-N）的衔接蛋白增加得到抑制。此外，rhGDF15 处理可激活抑制性磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）信号通路。体外通过脂多糖（LPS）诱导人支气管上皮细胞过表达 GDF15 也得到了同样的结果，并且应用 PI3K 通路抑制剂后 GDF15 的作用被逆转。因此，GDF15 可通过 PI3K/AKT 信号通路抑制肥胖型哮喘小鼠细胞焦亡来保护气道。
