アルコール濫用による細胞・組織防御システムの破綻機構

1.明确了乙醇通过激活核因子-kappaB和激活Akt2诱导IAP对细胞存活系统的调节。在非酒精性脂肪性肝病小鼠模型中，急性乙醇处理未通过核因子-kappaB引起促炎反应，提示脂肪性肝病存在炎症紊乱。多不饱和脂肪酸可引起脂肪肝的严重炎症反应。多不饱和脂肪酸诱导肝细胞释放IL-10，可能诱导Kupffer细胞活化。我们建立了酒精性猝死模型。在该模型中，TLR4信号通路在死亡原因中不起重要作用。在脑挫伤模型中，预先注射乙醇可促进创伤性脑损伤后的脑水肿。促进脑水肿会导致死亡。乙醇注射后脑挫伤并未引起促炎细胞因子的释放和细胞生存信号转录因子--核因子-kappaB的激活。颅脑损伤后应用N-乙酰半胱氨酸治疗可减轻脑水肿以维持生存。建立激素性股骨头坏死动物模型。在该模型中，TLR4信号在股骨头坏死中起着至关重要的作用。

1. It was clarified that ethanol regulates cell survival system via induction of IAP by NF-kappaB activation and activation of Akt.2. In the nonalcoholic fatty liver disease murine model, acute ethanol treatment caused no proinflammatory response via NF-kappaB, suggesting that inflammatory disturbance occurs in fatty liver disease.3. Polyunsaturated fatty acids caused sever inflammation in fatty liver. Then polyunsaturated fatty acid induced IL-10 release in hepatocytes, whichi may induce Kupffer cell activation.4. We established alcohol-related sudden death model. In this model, TLR4 signaling pathway did not play an important role in cause of death.5. In brain contusion model, prior ethanol injection promotes brain edema after traumatic brain injury. Promoting brain edema results in death. Brain contusion after ethanol injection did not cause any release in proinflammatory cytokines and activation of NF-kappaB, a cell survival signal transcription factor. N-acetyl cystine treatment after TBI reduced brain edema to keep survival.6. We established a model with steroid-induced osteonecrosis of femoral head. In this model, TLR4 signaling plays a crucial role in osteonecrosis of femoral head.