Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province 350117, PR China.
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province 350117, PR China.
Int Immunopharmacol. 2024 Nov 15;141:112907. doi: 10.1016/j.intimp.2024.112907. Epub 2024 Aug 18.
Sepsis, characterized by high mortality rates, causes over 50 % of acute lung injury (ALI) cases, primarily due to the heightened susceptibility of the lungs during this condition. Suppression of the excessive inflammatory response is critical for improving the survival of patients with sepsis; nevertheless, no specific anti-sepsis drugs exist. Huperzine A (HupA) exhibits neuroprotective and anti-inflammatory properties; however, its underlying mechanisms and effects on sepsis-induced ALI have yet to be elucidated. In this study, we demonstrated the potential of HupA for treating sepsis and explored its mechanism of action. To investigate the in vivo impacts of HupA, a murine model of sepsis was induced through cecal ligation and puncture (CLP) in both wild-type (WT) and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. Our results showed that HupA ameliorates sepsis-induced acute lung injury by activating the α7nAChR. We used the CLP sepsis model in wild-type and α7nAChR mice and found that HupA significantly increased the survival rate through α7nAChR, reduced the pro-inflammatory cytokine levels and oxidative stress, ameliorated histopathological lung injury, altered the circulating immune cell composition, regulated gut microbiota, and promoted short-chain fatty acid production through α7nAChR in vivo. Additionally, HupA inhibited Toll-like receptor NF-κB signaling by upregulating the α7nAChR/protein kinase B/glycogen synthase kinase-3 pathways. Our data elucidate HupA's mechanism of action and support a "new use for an old drug" in treating sepsis. Our findings serve as a basis for further in vivo studies of this drug, followed by application to humans. Therefore, the findings have the potential to benefit patients with sepsis.
脓毒症的死亡率很高，导致超过 50%的急性肺损伤（ALI）病例，主要是由于在这种情况下肺部的敏感性增加。抑制过度的炎症反应对于改善脓毒症患者的生存至关重要；然而，目前尚无特异性的抗脓毒症药物。石杉碱甲（HupA）具有神经保护和抗炎作用；然而，其潜在机制及其对脓毒症诱导的 ALI 的影响尚未阐明。在本研究中，我们证明了 HupA 治疗脓毒症的潜力，并探讨了其作用机制。为了研究 HupA 的体内影响，我们通过盲肠结扎和穿刺（CLP）在野生型（WT）和α7 烟碱型乙酰胆碱受体（α7nAChR）敲除小鼠中诱导了脓毒症小鼠模型。我们的结果表明，HupA 通过激活α7nAChR 改善脓毒症诱导的急性肺损伤。我们在野生型和α7nAChR 小鼠中使用 CLP 脓毒症模型，发现 HupA 通过α7nAChR 显著提高存活率，降低促炎细胞因子水平和氧化应激，改善组织病理学肺损伤，改变循环免疫细胞组成，调节肠道微生物群，并通过体内α7nAChR 促进短链脂肪酸产生。此外，HupA 通过上调α7nAChR/蛋白激酶 B/糖原合酶激酶-3 途径抑制 Toll 样受体 NF-κB 信号。我们的数据阐明了 HupA 的作用机制，并支持将其“旧药新用”治疗脓毒症。我们的发现为该药物的进一步体内研究提供了基础，并随后应用于人类。因此，这些发现有可能使脓毒症患者受益。
