Absence of peroxisome proliferators-activated receptors (PPAR) α enhanced the multiple organ failure induced by zymosan
Absence of peroxisome proliferators-activated receptors (PPAR) α enhanced the multiple organ failure induced by zymosan
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DOI：
10.1097/01.shk.0000230299.78515.2c
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发表时间：
2006-11-01
期刊：
影响因子：
3.1
通讯作者：
Cuzzocrea, Salvatore
中科院分区：
文献类型：
--
作者：
Di Paola, Rosanna;Esposito, Emanuela;Cuzzocrea, Salvatore
过氧化物酶体增殖物激活受体(PPAR)α是核受体超家族中的一员，与维甲酸、类固醇和甲状腺激素受体相关的配体依赖的转录因子。本研究旨在探讨PPAR-α受体在酵母多糖诱导的多器官功能障碍综合征(MODS)中的作用。通过腹腔注射酵母多糖(500 mg/kg)诱导MODS模型。在PPAR-α野生型(PPAR-αWT)和IPPAR-α基因敲除(PPAR-αKO)小鼠中，在给药18小时后进行评估，并监测12天(体重下降和死亡率)。酵母多糖对野生型小鼠的肝脏、肾脏、胰腺和小肠均有损害，并可引起严重炎症反应。在酵母多糖处理的野生型小鼠中，髓过氧化物酶活性，中性粒细胞渗透的指示，和脂质过氧化作用显著增加。野生型小鼠的酵母多糖也引起了血浆亚硝酸盐/硝酸盐水平的显著升高。免疫组织化学检测显示，酵母多糖处理的野生型小鼠肠道中对硝基酪氨酸和Fas配体的免疫反应明显增强。相比之下，酵母多糖处理的PPAR-αKO小鼠肠组织中(1)腹膜炎症和组织损伤，(2)硝基酪氨酸形成和Fas配体表达，(3)中性粒细胞浸润程度明显增强。酵母多糖处理的PPAR-αKO小鼠的死亡率也显著增加。综上所述，本研究清楚地表明，PPAR-α途径调节与酵母多糖诱导的非感染性休克相关的MODS的程度。
The peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study is to evaluate the role of PPAR-alpha receptor on the development of multiple-organ dysfunction syndrome (MODS) induced by zymosan. MODS was induced by peritoneal injection of zymosan (dose, 500 mg/kg i.p. as a suspension in saline) in PPAR-alpha wild-type (PPAR-alpha WT) and IPPAR-alpha knockout (PPAR-alpha KO) mice, was assessed 18 h after the administration of zymosan, and was monitored for 12 days (for loss of body weight and mortality). A severe inflammatory process, induced by zymosan administration in wild-type mice, coincided with the damage of liver, kidney, pancreas, and small intestine. Myeloperoxidase activity, indicative of neutrophil infiltration, and lipid peroxidation were significantly increased in zymosan-treated wild-type mice. Zymosan in the wild-type mice also induced a significant increase in the plasma levels of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine and Fas ligand in the intestine of zymosan-treated wild-type mice. In contrast, the degree of (1) peritoneal inflammation and tissue injury, (2) nitrotyrosine formation and Fas ligand expression, and (3) neutrophil infiltration were markedly enhanced in intestinal tissue obtained from zymosan-treated PPAR-alpha KO mice. Zymosan-treated PPAR-alpha KO mice also showed a significantly increased mortality. Taken together, the present study clearly demonstrates that PPAR-alpha pathway modulates the degree of MODS associated with zymosan-induced nonseptic shock.