Li Fen, Qin Na, Yu Yiqin, Dong Rui, Li Xiaojie, Gong Shenhai, Zeng Zhenhua, Huang Lin, Yang Hong
Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
The Third Clinical College of Southern Medical University, Guangzhou, China.
Arch Med Sci. 2024 Jun 28;20(3):984-996. doi: 10.5114/aoms/174264. eCollection 2024.
Recently, NLR family pyrin domain containing 3 (NLRP3) and pyroptosis have been reported to be involved in traumatic brain injury-induced acute lung injury (TBI-ALI). Studies have shown that triggering receptor expressed on myeloid cells-1 (TREM-1) may be one of the upstream molecules regulating NLRP3/pyroptosis, and 5-hydroxytryptamine type 3-receptor (5-HT3R) antagonists can inhibit NLRP3/pyroptosis. However, the role of TRME-1 in TBI-ALI, the therapeutic effect of 5-HT3R inhibition on TBI-ALI and its mechanism are still unclear. Therefore, this study aimed to evaluate the protective effect of ondansetron, a 5-HT3 inhibitor, on TBI-ALI, and to explore whether the underlying mechanism is related to the regulation of TREM-1.
A TBI-ALI rat model was constructed via lateral fluid percussion (LFP) brain injury, and either TREM-1 inhibitor (LP17) or ondansetron was administered as needed.
TBI induced NLRP3 inflammasome, pyroptosis, and TREM-1 activation in rat lung tissues in a time-dependent manner. Inhibition of TREM-1 activity attenuated TBI-ALI; this is evident from reduced pathological scores, wet/dry ratios, and bronchoalveolar lavage fluid protein levels and alleviated NLRP3 inflammasome/pyroptosis. In addition, ondansetron reduced NLRP3 inflammasome/pyroptosis and alleviated TBI-ALI. Moreover, ondansetron reduced TREM-1 activation in macrophages and lung tissue.
Ondansetron alleviated TBI-ALI. In terms of mechanism, TREM-1 promotes TBI-ALI via the NLRP3-related pyroptosis pathway, and the protective effect of ondansetron on TBI-ALI may be related to the inhibition of TREM-1.
最近，有报道称含NLR家族pyrin结构域蛋白3（NLRP3）和细胞焦亡参与创伤性脑损伤诱导的急性肺损伤（TBI-ALI）。研究表明，髓系细胞触发受体-1（TREM-1）可能是调节NLRP3/细胞焦亡的上游分子之一，5-羟色胺3型受体（5-HT3R）拮抗剂可抑制NLRP3/细胞焦亡。然而，TREM-1在TBI-ALI中的作用、5-HT3R抑制对TBI-ALI的治疗效果及其机制仍不清楚。因此，本研究旨在评估5-HT3抑制剂昂丹司琼对TBI-ALI的保护作用，并探讨其潜在机制是否与TREM-1的调节有关。
通过侧方流体冲击（LFP）脑损伤构建TBI-ALI大鼠模型，并根据需要给予TREM-1抑制剂（LP17）或昂丹司琼。
TBI以时间依赖性方式诱导大鼠肺组织中NLRP3炎性小体、细胞焦亡和TREM-1激活。抑制TREM-1活性可减轻TBI-ALI；这从病理评分降低、湿/干比和支气管肺泡灌洗蛋白水平降低以及NLRP3炎性小体/细胞焦亡减轻中明显可见。此外，昂丹司琼降低了NLRP3炎性小体/细胞焦亡并减轻了TBI-ALI。而且，昂丹司琼降低了巨噬细胞和肺组织中TREM-1的激活。
昂丹司琼减轻了TBI-ALI。就机制而言，TREM-1通过NLRP3相关的细胞焦亡途径促进TBI-ALI，昂丹司琼对TBI-ALI的保护作用可能与抑制TREM-1有关。
