Department of Experimental Medicine, Section of Pharmacology 'L.Donatelli', Excellence Centre for Cardiovascular Diseases, Second University of Naples, Italy.
Br J Pharmacol. 2011 Jun;163(3):609-23. doi: 10.1111/j.1476-5381.2011.01248.x.
Zymosan-induced non-septic shock is a multi-factorial pathology that involves several organs including the kidneys, liver and lungs. Its complexity and diversity presents a continuing therapeutic challenge. Given their pleiotropic effect, statins could be beneficial in non-septic shock. One of the molecular mechanisms underlying the anti-inflammatory effect of statins involves the peroxisome proliferator-activated receptor (PPAR) α. We used a zymosan-induced non-septic shock experimental model to investigate the role of PPARα in the anti-inflammatory effects of simvastatin.
Effects of simvastatin (5 or 10 mg·kg(-1) i.p.) were analysed in PPARα knock-out (KO) and PPARα wild type (WT) mice after zymosan or vehicle administration. Organ injury in lung, liver, kidney and intestine was evaluated by immunohistology. PPARα mRNA expression and nuclear factor-κB activation were evaluated in all experimental groups, 18 h after study onset. Cytokine levels were measured in plasma, and nitrite/nitrate in plasma and peritoneal exudate. Nitric oxide synthase, nitrotyrosine and poly ADP-ribose were localized by immunohistochemical methods.
Simvastatin significantly and dose-dependently increased the zymosan-induced expression of PPARα levels in all tissues analysed. It also dose-dependently reduced systemic inflammation and the organ injury induced by zymosan in lung, liver, intestine and kidney. These effects were observed in PPARαWT mice and in PPARαKO mice.
Simvastatin protected against the molecular and cellular damage caused by systemic inflammation in our experimental model. Our results also provide new information regarding the role of PPARα in the anti-inflammatory effects of statins.
酵母聚糖诱导的非感染性休克是一种多因素病理，涉及多个器官，包括肾脏、肝脏和肺部。其复杂性和多样性提出了持续的治疗挑战。鉴于他汀类药物的多效性，它们可能对非感染性休克有益。他汀类药物抗炎作用的分子机制之一涉及过氧化物酶体增殖物激活受体（PPAR）α。我们使用酵母聚糖诱导的非感染性休克实验模型来研究 PPARα 在辛伐他汀抗炎作用中的作用。
在酵母聚糖或载体给药后，分析了辛伐他汀（5 或 10 mg·kg(-1) i.p.）对 PPARα 敲除（KO）和 PPARα 野生型（WT）小鼠的影响。通过免疫组织化学评估肺、肝、肾和肠的器官损伤。在研究开始后 18 小时，评估所有实验组中的 PPARα mRNA 表达和核因子-κB 激活。测量血浆中的细胞因子水平，以及血浆和腹膜渗出物中的亚硝酸盐/硝酸盐。通过免疫组织化学方法定位一氧化氮合酶、硝基酪氨酸和多聚 ADP-核糖。
辛伐他汀显著且剂量依赖性地增加了所有分析组织中酵母聚糖诱导的 PPARα 水平的表达。它还剂量依赖性地降低了系统性炎症和酵母聚糖诱导的肺、肝、肠和肾损伤。这些作用在 PPARαWT 小鼠和 PPARαKO 小鼠中均观察到。
辛伐他汀在我们的实验模型中保护免受系统性炎症引起的分子和细胞损伤。我们的结果还提供了关于 PPARα 在他汀类药物抗炎作用中的作用的新信息。
