NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113332. doi: 10.1016/j.intimp.2024.113332. Epub 2024 Oct 11.
The clinical syndrome of sepsis arises from severe infection, triggering an abnormal immune response that can lead to multiple organ dysfunction and ultimately the death of the host. Current therapies for sepsis are often limited in efficacy and fail to target the complex interplay of infection, inflammation and coagulation, leading to high mortality rates, which underscores the urgent need for novel therapeutics to combat sepsis. We previously identified Cath-HG, a compound capable of alleviating platelet dysfunction by suppressing GPVI-mediated platelet activation, thereby improving the survival of septic mice subjected to cecal ligation and puncture. Here, we further explored the antimicrobial, anti-inflammatory, LPS-neutralizing and anticoagulant properties of Cath-HG, as well as its protective effects in LPS-induced septic mice. Our results demonstrated that Cath-HG can bind to LPS, aggregate bacteria, and disrupt bacterial cell membranes, subsequently resulting in microbial death. Unlike most other Cathelicidins, Cath-HG displayed anticoagulation properties by regulating the enzymes plasmin, thrombin, β-tryptase, chymase and tissue plasminogen activator. In septic mice, Cath-HG provided protection against sepsis induced by LPS injection and exhibited bactericidal killing, LPS neutralization and inhibition of coagulation and MAPK signal transduction. Furthermore, Cath-HG obviously reduced the expression of pro-inflammatory cytokines and improved the pathological manifestations of tissue injury across multiple organs. Thus, Cath-HG emerges as a promising drug candidate for protecting against sepsis.
脓毒症的临床综合征源于严重感染，引发异常免疫反应，导致多器官功能障碍，最终宿主死亡。目前脓毒症的治疗方法往往疗效有限，不能针对感染、炎症和凝血的复杂相互作用，导致高死亡率，这突显了迫切需要新的疗法来对抗脓毒症。我们之前发现 Cath-HG 是一种能够通过抑制 GPVI 介导的血小板激活来缓解血小板功能障碍的化合物，从而提高接受盲肠结扎和穿刺的脓毒症小鼠的存活率。在这里，我们进一步探索了 Cath-HG 的抗菌、抗炎、LPS 中和和抗凝特性，以及它在 LPS 诱导的脓毒症小鼠中的保护作用。我们的结果表明，Cath-HG 可以与 LPS 结合，聚集细菌并破坏细菌细胞膜，随后导致微生物死亡。与大多数其他 Cathelicidins 不同，Cath-HG 通过调节纤溶酶、凝血酶、β-胰蛋白酶、糜蛋白酶和组织纤溶酶原激活物等酶来显示抗凝特性。在脓毒症小鼠中，Cath-HG 对 LPS 注射引起的脓毒症提供了保护作用，并表现出杀菌杀伤、LPS 中和以及抑制凝血和 MAPK 信号转导的作用。此外，Cath-HG 明显降低了促炎细胞因子的表达，并改善了多个器官的组织损伤的病理表现。因此，Cath-HG 作为一种有前途的药物候选物，可用于预防脓毒症。
