Billiar T R, Curran R D, Stuehr D J, West M A, Bentz B G, Simmons R L
Department of Surgery, University of Pittsburgh, Pennsylvania 15261.
J Exp Med. 1989 Apr 1;169(4):1467-72. doi: 10.1084/jem.169.4.1467.
The hepatic failure associated with severe sepsis is characterized by specific, progressive, and often irreversible defects in hepatocellular metabolism (1). Although the etiologic microbe can often be identified, the direct causes and mechanisms of the hepatocellular dysfunction are poorly understood. We have hypothesized that Kupffer cells (KC), which interact with ambient septic stimuli, respond by providing signals to adjacent hepatocytes (HC) in sepsis . Furthermore, we have provided evidence (2, 3) that KC activated by LPS from Gram-negative bacteria can induce profound changes in the function of neighboring HC in coculture. In our model, coculture of either KC (2) or peritoneal macrophages (Mphi)(3) with HC normally promotes HC protein synthesis ([(3)H]leucine incorporation). The addition of LPS or killed Escherichia colt' to such cocultures induces a profound decrease in HC protein synthesis, as well as qualitative changes ([(35)S]methionine, SDS-gel electrophoresis) in protein synthesis without inducing HC death (2, 3) . In this report we show that the inhibition in protein synthesis is mediated via an L-arginine-dependent mechanism. The metabolism of L-arginine by activated Mphi to substances with cytostatic and even lethal effects on target cells is a relatively recent discovery. After the description by Stuehr and Marletta (4, 5) that LPS- triggered Mphi produced nitrite/nitrate (NO(2)(-)/NO(3)(-)), Hibbs et al. (6, 7) and Iyengar et al. (8) demonstrated that L-arginine was the substrate for the formation of both these nitrogen end products and citrulline. A role for the arginine-dependent mechanism in Mphi tumor cytotoxicity (6, 7) and microbiostatic activity (9) has been suggested. However, the in vivo functions of this novel Mphi mechanism have not yet been defined, but it is possible that there are both physiologic as well as pathologic roles. Our in vitro results raise the possibility that some metabolic responses to microbial invasion maybe partially mediated by the L-arginine-dependent mechanism. What other metabolic responses are affected and the possible pathologic consequences remain to be studied.
与严重脓毒症相关的肝衰竭的特征是肝细胞代谢存在特定、渐进且往往不可逆的缺陷（1）。尽管通常可以识别出病因微生物，但肝细胞功能障碍的直接原因和机制仍知之甚少。我们推测，与周围脓毒症刺激相互作用的库普弗细胞（KC）在脓毒症中通过向相邻肝细胞（HC）提供信号做出反应。此外，我们已经提供证据（2,3）表明，革兰氏阴性菌的脂多糖激活的KC可在共培养中诱导相邻HC功能发生深刻变化。在我们的模型中，KC（2）或腹膜巨噬细胞（Mphi）（3）与HC共培养通常会促进HC蛋白质合成（[³H]亮氨酸掺入）。向这种共培养物中添加脂多糖或灭活的大肠杆菌会导致HC蛋白质合成显著减少，以及蛋白质合成发生定性变化（[³⁵S]甲硫氨酸，SDS凝胶电泳），但不会诱导HC死亡（2,3）。在本报告中，我们表明蛋白质合成的抑制是通过L-精氨酸依赖性机制介导的。活化的Mphi将L-精氨酸代谢为对靶细胞具有细胞毒性甚至致死作用的物质是一个相对较新的发现。在Stuehr和Marletta（4,5）描述脂多糖触发的Mphi产生亚硝酸盐/硝酸盐（NO₂⁻/NO₃⁻）之后，Hibbs等人（6,7）和Iyengar等人（8）证明L-精氨酸是这两种氮终产物和瓜氨酸形成过程的底物。有人提出精氨酸依赖性机制在Mphi肿瘤细胞毒性（6,7）和微生物抑制活性（9）中起作用。然而，这种新型Mphi机制在体内的功能尚未明确，但可能存在生理和病理作用。我们的体外研究结果提出了一种可能性，即对微生物入侵的一些代谢反应可能部分由L-精氨酸依赖性机制介导。还有哪些其他代谢反应受到影响以及可能的病理后果仍有待研究。
