Saadane A, Delautier D, Leboucher J, Kharbajou M, Feldmann G, Lardeux B, Bleiberg-Daniel F
Laboratoire de Biologie Cellulaire, Unité 327 de l'Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Xavier Bichat, Université Paris 7, France.
Shock. 1999 Jun;11(6):429-35.
In systemic or localized acute inflammation, liver ribosomal RNA (rRNA) and protein contents increase. We first determined whether changes in RNA, more specifically rRNA, and protein breakdown rates were involved in the accumulation of both types of macromolecules 24 h after induction of endotoxemia. Liver RNA and protein contents were enhanced by 35 and 19%, respectively, in the endotoxemic rats. RNA and protein degradation rates measured during in situ cyclic perfusions of the livers were significantly higher in the endotoxemic rats than in the controls (42 and 46%, respectively). In order to check that the stimulation of RNA and protein degradation corresponded to an activation of the hepatocyte autophagic pathway, the fractional cytoplasmic volume (FCV) of autophagosomes, digestive autophagic vacuoles and dense bodies was measured by morphometry in electron microscopy. The FCV of the sum of these lysosomal structures was significantly increased in the endotoxemic rats. We next tried to identify the factor(s) responsible for the high breakdown rates. The increase in macromolecular degradation did not result from reduced portal amino acid supply. The effects of dexamethasone, interleukin-6, interleukin-1beta, and tumor necrosis factor alpha on RNA degradation were then investigated in primary cultures of hepatocytes isolated from control rats. Only dexamethasone stimulated RNA breakdown. Finally, pretreatment of endotoxemic rats with RU 38486, a glucocorticoid receptor antagonist, completely abolished the stimulation of RNA degradation observed in the sham-gavaged LPS-treated rats. Our data suggest an important role of glucocorticoids in the high levels of RNA and protein breakdown in endotoxemic rats.
在全身性或局部性急性炎症中，肝脏核糖体RNA（rRNA）和蛋白质含量会增加。我们首先确定RNA（更具体地说是rRNA）和蛋白质分解速率的变化是否与内毒素血症诱导24小时后这两种大分子的积累有关。在内毒素血症大鼠中，肝脏RNA和蛋白质含量分别提高了35%和19%。在内毒素血症大鼠肝脏原位循环灌注期间测得的RNA和蛋白质降解速率显著高于对照组（分别为42%和46%）。为了验证RNA和蛋白质降解的刺激是否对应于肝细胞自噬途径的激活，通过电子显微镜形态计量法测量了自噬体、消化性自噬泡和致密体的细胞质分数体积（FCV）。在内毒素血症大鼠中，这些溶酶体结构总和的FCV显著增加。接下来，我们试图确定导致高分解速率的因素。大分子降解的增加并非由于门静脉氨基酸供应减少所致。随后在从对照大鼠分离的肝细胞原代培养物中研究了地塞米松、白细胞介素-6、白细胞介素-1β和肿瘤坏死因子α对RNA降解的影响。只有地塞米松刺激了RNA分解。最后，用糖皮质激素受体拮抗剂RU 38486对内毒素血症大鼠进行预处理，完全消除了在假灌胃LPS处理大鼠中观察到的RNA降解刺激。我们的数据表明糖皮质激素在内毒素血症大鼠高水平的RNA和蛋白质分解中起重要作用。
