Abdelrahman Maha, Collin Marika, Thiemermann Christoph
Centre for Experimental Medicine, Nephrology and Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, EC1M 6BQ, United Kingdom.
Shock. 2004 Dec;22(6):555-61. doi: 10.1097/01.shk.0000144132.13900.24.
The cyclopentenone prostaglandin 15-deoxyDelta12,14PGJ2 (15d-PGJ2) exerts potent anti-inflammatory effects in vivo, which are in part caused by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Here we investigate the effects of 15d-PGJ2 on the multiple organ injury/dysfunction associated with severe hemorrhage and resuscitation. Male Wistar rats were subjected to hemorrhage (to lower mean arterial blood pressure to 45 mmHg) for 90 min and subsequently resuscitated with shed blood for 4 h. Rats were treated with either 15d-PGJ2 (0.3 mg/kg i.v.) or its vehicle (10% dimethyl sulfoxide) at 30 min before the hemorrhage. In some experiments, the selective PPAR-gamma antagonist GW9662 (1 mg/kg i.v.) or its vehicle (10% dimethyl sulfoxide) was given 45 min before the hemorrhage. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) urea and creatinine and, hence renal dysfunction; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and, hence, hepatic injury. The potent PPAR-gamma agonist 15d-PGJ2 abolished the renal dysfunction and largely reduced the liver injury caused by hemorrhagic shock. In addition, 15d-PGJ2 also attenuated the lung and intestinal injury (determined by histology) caused by hemorrhage and resuscitation. The specific PPAR-gamma antagonist GW9662 reduced the protective effects afforded by 15d-PGJ2. 15d-PGJ2 did not affect the delayed fall in blood pressure caused by hemorrhage and resuscitation. The mechanisms of the protective effect of this cyclopentenone prostaglandin are, at least in part, PPAR-gamma dependent, as the protection afforded by 15d-PGJ2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-PGJ2 or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with hemorrhagic shock.
环戊烯酮前列腺素15-脱氧Δ12,14前列腺素J2（15d-PGJ2）在体内具有强大的抗炎作用，部分是由过氧化物酶体增殖物激活受体γ（PPAR-γ）的激活所致。在此，我们研究15d-PGJ2对与严重出血和复苏相关的多器官损伤/功能障碍的影响。雄性Wistar大鼠接受90分钟的出血处理（使平均动脉血压降至45 mmHg），随后用自体血复苏4小时。在出血前30分钟，大鼠接受15d-PGJ2（0.3 mg/kg静脉注射）或其溶媒（10%二甲基亚砜）治疗。在一些实验中，在出血前45分钟给予选择性PPAR-γ拮抗剂GW9662（1 mg/kg静脉注射）或其溶媒（10%二甲基亚砜）。出血和复苏导致血清中（a）尿素和肌酐水平升高，进而引起肾功能障碍；丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）升高，进而导致肝损伤。强效PPAR-γ激动剂15d-PGJ2消除了肾功能障碍，并在很大程度上减轻了出血性休克引起的肝损伤。此外，15d-PGJ2还减轻了出血和复苏引起的肺和肠道损伤（通过组织学确定）。特异性PPAR-γ拮抗剂GW9662降低了15d-PGJ2提供的保护作用。15d-PGJ2不影响出血和复苏引起的血压延迟下降。这种环戊烯酮前列腺素的保护作用机制至少部分依赖于PPAR-γ，因为PPAR-γ拮抗剂GW9662降低了15d-PGJ2提供的保护作用。我们提出，15d-PGJ2或其他PPAR-γ配体可能对治疗与出血性休克相关的器官损伤有用。
