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Targeting of G-protein coupled receptors in sepsis.
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2020-03-19 , DOI: 10.1016/j.pharmthera.2020.107529
Abdul Rehman 1 , Noor Ul-Ain Baloch 1 , John P Morrow 2 , Pál Pacher 3 , György Haskó 4
Affiliation  

The Third International Consensus Definitions (Sepsis-3) define sepsis as life-threatening multi-organ dysfunction caused by a dysregulated host response to infection. Sepsis can progress to septic shock—an even more lethal condition associated with profound circulatory, cellular and metabolic abnormalities. Septic shock remains a leading cause of death in intensive care units and carries a mortality of almost 25%. Despite significant advances in our understanding of the pathobiology of sepsis, therapeutic interventions have not translated into tangible differences in the overall outcome for patients. Clinical trials of antagonists of various pro-inflammatory mediators in sepsis have been largely unsuccessful in the past. Given the diverse physiologic roles played by G-protein coupled receptors (GPCR), modulation of GPCR signaling for the treatment of sepsis has also been explored. Traditional pharmacologic approaches have mainly focused on ligands targeting the extracellular domains of GPCR. However, novel techniques aimed at modulating GPCR intracellularly through aptamers, pepducins and intrabodies have opened a fresh avenue of therapeutic possibilities. In this review, we summarize the diverse roles played by various subfamilies of GPCR in the pathogenesis of sepsis and identify potential targets for pharmacotherapy through these novel approaches.



中文翻译:


败血症中 G 蛋白偶联受体的靶向。



第三个国际共识定义 (Sepsis-3) 将脓毒症定义为由宿主对感染反应失调引起的危及生命的多器官功能障碍。脓毒症可发展为脓毒性休克,这是一种与严重的循环、细胞和代谢异常相关的更致命的疾病。感染性休克仍然是重症监护病房死亡的主要原因,死亡率接近 25%。尽管我们对脓毒症病理学的理解取得了重大进展,但治疗干预措施尚未转化为患者总体结果的明显差异。过去,各种促炎介质拮抗剂治疗脓毒症的临床试验基本上不成功。鉴于 G 蛋白偶联受体 (GPCR) 发挥的多种生理作用,人们还探索了调节 GPCR 信号传导来治疗脓毒症。传统的药理学方法主要集中于针对 GPCR 细胞外结构域的配体。然而,旨在通过适体pepducins胞内抗体在细胞内调节 GPCR 的新技术开辟了一条新的治疗可能性途径。在这篇综述中,我们总结了 GPCR 各个亚家族在脓毒症发病机制中发挥的不同作用,并通过这些新方法确定了药物治疗的潜在靶点。

更新日期:2020-03-19
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