Carrillo-Vico Antonio, Lardone Patricia J, Naji Latifa, Fernández-Santos José M, Martín-Lacave Inés, Guerrero Juan M, Calvo Juan R
Department of Medical Biochemistry and Molecular Biology, The University of Seville School of Medicine and Virgen Macarena Hospital, Seville, Spain.
J Pineal Res. 2005 Nov;39(4):400-8. doi: 10.1111/j.1600-079X.2005.00265.x.
Septic shock, the most severe problem of sepsis, is a lethal condition caused by the interaction of a pathogen-induced long chain of sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. The lethal effects of septic shock are associated with the production and release of numerous pro-inflammatory biochemical mediators including cytokines, nitric oxide and toxic oxygen and nitrogen radicals, together with development of massive apoptosis. As melatonin has remarkable properties as a cytokine modulator, antioxidant and anti-apoptotic agent, the present study was designed to evaluate the possible protective effect of melatonin against LPS-induced septic shock in Swiss mice. We observed that intraperitoneally (i.p.) administered-melatonin (10 mg/kg) 30 min prior, and 1 hr after i.p. LPS injection (0.75 mg/animal) markedly protected mice from the LPS lethal effects with 90% survival rates for melatonin and 20% for LPS-injected mice after 72 hr. The melatonin effect was mediated by modulating the release of pro-/anti-inflammatory cytokine levels, protection from oxidative damage and counteracting apoptotic cell death. Melatonin was able to partially counteract the increase in LPS-induced pro-inflammatory cytokine levels such as tumor necrosis factor-alpha, IL-12 and interferon-gamma at the local site of injection, while it increased the production of the anti-inflammatory cytokine IL-10 both locally and systemically. Furthermore, melatonin inhibited the LPS-induced nitrite/nitrate and lipid peroxidation levels in brain and liver and counteracted the sepsis-associated apoptotic process in spleen. In conclusion, we have demonstrated that melatonin improves the survival of mice with septic shock via its pleiotropic functions as an immunomodulator, antioxidant and anti-apoptotic mediator.
脓毒症休克是脓毒症最严重的问题，是一种由病原体诱导的免疫细胞、上皮细胞、内皮细胞和神经内分泌系统中一系列连续的细胞内事件相互作用所导致的致命病症。脓毒症休克的致死效应与多种促炎生化介质的产生和释放有关，这些介质包括细胞因子、一氧化氮以及有毒的氧自由基和氮自由基，同时还伴随着大量细胞凋亡的发生。由于褪黑素作为一种细胞因子调节剂、抗氧化剂和抗凋亡剂具有显著特性，本研究旨在评估褪黑素对瑞士小鼠脂多糖诱导的脓毒症休克可能具有的保护作用。我们观察到，在腹腔注射脂多糖（0.75毫克/只动物）前30分钟及注射后1小时腹腔注射褪黑素（10毫克/千克），能显著保护小鼠免受脂多糖的致死效应，72小时后，注射褪黑素的小鼠存活率为90%，而注射脂多糖的小鼠存活率为20%。褪黑素的作用是通过调节促炎/抗炎细胞因子水平的释放、防止氧化损伤以及对抗凋亡性细胞死亡来介导的。褪黑素能够部分抵消脂多糖诱导的注射局部促炎细胞因子水平的升高，如肿瘤坏死因子-α、白细胞介素-12和干扰素-γ，同时它还能在局部和全身增加抗炎细胞因子白细胞介素-10的产生。此外，褪黑素抑制了脂多糖诱导的脑和肝脏中亚硝酸盐/硝酸盐水平及脂质过氧化水平，并对抗了脾脏中与脓毒症相关的凋亡过程。总之，我们已经证明褪黑素通过其作为免疫调节剂、抗氧化剂和抗凋亡介质的多效性功能提高了脓毒症休克小鼠的存活率。
