Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Int Immunol. 2011 Mar;23(3):185-93. doi: 10.1093/intimm/dxq471.
Sepsis is a systemic disease resulting from harmful host response to bacterial infections. During the exacerbation of severe sepsis or septic shock, apoptosis of endothelial cells is induced in susceptible organs such as the lung and liver and triggers microcirculatory disorder and organ dysfunction. LPS, an outer membrane component of Gram-negative bacteria, is one of the major virulence factors for the pathogenesis. We previously reported that LL-37, a human anti-microbial cathelicidin peptide, potently neutralizes the biological activity of LPS and protects mice from lethal endotoxin shock. However, the effect of LL-37 on the LPS-induced endothelial cell apoptosis remains to be clarified. In this study, to further elucidate the action of LL-37 on severe sepsis/endotoxin shock, we investigated the effects of LL-37 on the LPS-induced endothelial cell apoptosis in vitro and in vivo using lung-derived normal human microvascular blood vessel endothelial cells (HMVEC-LBls) and D-galactosamine hydrochloride (D-GalN)-sensitized murine endotoxin shock model. LL-37 suppressed the LPS-induced apoptosis of HMVEC-LBls. In addition, LL-37 inhibited the binding of LPS possibly to the LPS receptors (CD14 and toll-like receptor 4) expressed on the cells. Thus, LL-37 can suppress the LPS-induced apoptosis of HMVEC-LBls via the inhibition of LPS binding to the cells. Furthermore, LL-37 drastically suppressed the apoptosis of hepatic endothelial cells as well as hepatocytes in the liver of murine endotoxin shock model. Together, these observations suggest that LL-37 could suppress the LPS-induced apoptosis of endothelial cells, thereby attenuating lethal sepsis/endotoxin shock.
脓毒症是一种全身性疾病，是由宿主对细菌感染的有害反应引起的。在严重脓毒症或感染性休克恶化期间，肺和肝等易感器官中的内皮细胞会发生凋亡，并引发微循环障碍和器官功能障碍。脂多糖（LPS）是革兰氏阴性菌的外膜成分之一，是导致发病的主要毒力因子之一。我们之前曾报道过，人抗菌肽 LL-37 可有效中和 LPS 的生物学活性，并保护小鼠免受致死性内毒素休克的影响。然而，LL-37 对 LPS 诱导的内皮细胞凋亡的影响仍有待阐明。在这项研究中，为了进一步阐明 LL-37 在严重脓毒症/内毒素休克中的作用，我们使用肺源性正常人类微血管血管内皮细胞（HMVEC-LBls）和 D-半乳糖胺盐酸盐（D-GalN）敏化的小鼠内毒素休克模型，在体外和体内研究了 LL-37 对 LPS 诱导的内皮细胞凋亡的影响。LL-37 抑制了 LPS 诱导的 HMVEC-LBls 凋亡。此外，LL-37 可能抑制了 LPS 与细胞表面表达的 LPS 受体（CD14 和 Toll 样受体 4）的结合。因此，LL-37 可以通过抑制 LPS 与细胞的结合来抑制 LPS 诱导的 HMVEC-LBls 凋亡。此外，LL-37 大大抑制了小鼠内毒素休克模型肝脏中肝内皮细胞和肝细胞的凋亡。总之，这些观察结果表明，LL-37 可以抑制 LPS 诱导的内皮细胞凋亡，从而减轻致命性脓毒症/内毒素休克。
