肥胖相关性哮喘:基于病理生理学的现有和新兴治疗方法概述。
Obesity-related Asthma: A Pathobiology-based Overview of Existing and Emerging Treatment Approaches.
机构信息
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
Division of Pulmonary Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
出版信息
Am J Respir Crit Care Med. 2024 Nov 15;210(10):1186-1200. doi: 10.1164/rccm.202406-1166SO.
Although obesity-related asthma is associated with worse asthma outcomes, optimal treatment approaches for this complex phenotype are still largely unavailable. This state-of-the-art review article synthesizes evidence for existing and emerging treatment approaches for obesity-related asthma and highlights pathways that offer potential targets for novel therapeutics. Existing treatments targeting insulin resistance and obesity, including metformin and GLP-1 (glucagon-like-peptide 1) receptor agonists, have been associated with improved asthma outcomes, although GLP-1R agonist data in asthma are limited to individuals with comorbid obesity. Monoclonal antibodies approved for treatment of moderate to severe asthma generally appear to be effective in individuals with obesity, although this is based on retrospective or secondary analysis of clinical trials; moreover, although most of these asthma biologics are approved for use in the pediatric population, the impact of obesity on their efficacy has not been well studied in youth. Potential therapeutic targets being investigated include IL-6, arginine metabolites, nitro-fatty acids, and mitochondrial antioxidants, with clinical trials for each currently underway. Potential therapeutic targets include adipose tissue eosinophils and the GLP-1-arginine-advanced glycation end products axis, although data in humans are still needed. Finally, transcriptomic and epigenetic studies of "obese asthma" demonstrate enrichment of IFN-related signaling pathways, Rho-GTPase pathways, and integrins, suggesting that these too could represent future treatment targets. We advocate for further study of these potential therapeutic mechanisms and continued investigation of the distinct inflammatory pathways characteristic of obesity-related asthma, to facilitate effective treatment development for this unique asthma phenotype.
尽管与肥胖相关的哮喘与更差的哮喘结局相关,但针对这种复杂表型的最佳治疗方法仍在很大程度上尚未可知。本文是一篇最新综述,综合了现有和新兴的与肥胖相关的哮喘治疗方法的证据,并强调了为新型疗法提供潜在靶点的途径。现有的针对胰岛素抵抗和肥胖的治疗方法,包括二甲双胍和 GLP-1(胰高血糖素样肽 1)受体激动剂,已被证明与改善哮喘结局相关,尽管 GLP-1R 激动剂在哮喘中的数据仅限于合并肥胖的个体。批准用于治疗中重度哮喘的单克隆抗体在肥胖个体中似乎通常有效,尽管这是基于临床试验的回顾性或二次分析;此外,尽管这些哮喘生物制剂中的大多数都被批准用于儿科人群,但肥胖对其疗效的影响在青少年中尚未得到很好的研究。目前正在研究的潜在治疗靶点包括 IL-6、精氨酸代谢物、硝基脂肪酸和线粒体抗氧化剂,每个靶点都有临床试验正在进行。潜在的治疗靶点包括脂肪组织嗜酸性粒细胞和 GLP-1-精氨酸-晚期糖基化终产物轴,尽管人类仍需要相关数据。最后,“肥胖哮喘”的转录组和表观遗传研究表明 IFN 相关信号通路、Rho-GTPase 通路和整合素富集,这表明它们也可能成为未来的治疗靶点。我们主张进一步研究这些潜在的治疗机制,并继续研究与肥胖相关的哮喘特征相关的独特炎症途径,以促进针对这种独特哮喘表型的有效治疗方法的开发。