Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan ; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
PLoS One. 2013 Oct 18;8(10):e78861. doi: 10.1371/journal.pone.0078861. eCollection 2013.
Maraviroc is a CC-chemokine receptor 5 (CCR5) antagonist with potent antiviral and cancer preventive effects. Recent evidence suggests that the co-existence of CCR5 in various cell types is involved in inflammation. However, the effects that CCR5 antagonists produce in trauma-hemorrhage remain unknown. The peroxisome proliferator-activated receptor gamma (PPAR(γ)) pathway exerts anti-inflammatory effects in injury. In this study, we hypothesized that maraviroc administration in male rats, after trauma-hemorrhage, decreases cytokine production and protects against hepatic injury through a PPAR(γ)-dependent pathway. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes), followed by fluid resuscitation. During resuscitation, a single dose of maraviroc (3 mg/kg, intravenously) with and without a PPAR(γ) antagonist GW9662 (1 mg/kg, intravenously), GW9662 or vehicle was administered. Plasma alanine aminotransferase (ALT) with aspartate aminotransferase (AST) concentrations and various hepatic parameters were measured (n=8 rats/group) at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the maraviroc-treated rats subjected to trauma-hemorrhage. Maraviroc treatment also increased hepatic PPAR(γ) expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of GW9662 with maraviroc abolished the maraviroc-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of maraviroc administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through PPAR(γ)-dependent pathway.
马拉维若（Maraviroc）是一种 CCR5 趋化因子受体 5（CCR5）拮抗剂，具有强大的抗病毒和防癌作用。最近的证据表明，各种细胞类型中 CCR5 的共存与炎症有关。然而，CCR5 拮抗剂在创伤性失血性休克中的作用尚不清楚。过氧化物酶体增殖物激活受体γ（PPARγ）途径在损伤中发挥抗炎作用。在这项研究中，我们假设在创伤性失血性休克后，雄性大鼠给予马拉维若（Maraviroc）可通过 PPARγ 依赖性途径减少细胞因子的产生并防止肝损伤。雄性 Sprague-Dawley 大鼠接受创伤性失血性休克（平均血压维持在约 35-40mmHg 90 分钟），然后进行液体复苏。在复苏过程中，给予单剂量的马拉维若（Maraviroc）（3mg/kg，静脉内），并伴有和不伴有 PPARγ 拮抗剂 GW9662（1mg/kg，静脉内）、GW9662 或载体。复苏后 24 小时测量血浆丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）浓度以及各种肝参数（n=8 只大鼠/组）。结果表明，创伤性失血性休克增加了肝髓过氧化物酶活性、细胞间黏附分子-1 和白细胞介素-6 水平以及血浆 ALT 和 AST 浓度。与创伤性失血性休克的载体处理大鼠相比，这些参数在马拉维若处理的大鼠中得到了显著改善。与创伤性失血性休克的载体处理大鼠相比，马拉维若治疗还增加了肝 PPARγ 的表达。GW9662 与马拉维若联合给药消除了马拉维若对上述参数和肝损伤的有益作用。这些结果表明，马拉维若给药对创伤性失血性休克后肝损伤的缓解作用至少部分是通过 PPARγ 依赖性途径。
