Akerman P A, Cote P M, Yang S Q, McClain C, Nelson S, Bagby G, Diehl A M
Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205.
Hepatology. 1993 Jun;17(6):1066-73.
The pathogenesis of chronic alcoholic liver disease is uncertain, but it may reflect an impaired wound healing response to ethanol-induced liver injury. Cell-to-cell communication such as that mediated by the cytokine tumor necrosis factor is necessary for successful liver regeneration and complete recovery from liver injury. Hence disruption of intercellular regenerative signaling may contribute to the pathogenesis of chronic alcoholic liver disease. To test this hypothesis, the cytokine and regenerative responses triggered by partial hepatectomy were compared in ethanol-fed rats and isocalorically maintained, pair-fed controls. To further clarify the effect of ethanol on tumor necrosis factor-modulated regenerative effects, we evaluated some of the rats in each feeding group after pretreatment with antibodies to tumor necrosis factor. As expected, ethanol inhibited DNA synthesis and liver cell proliferation after partial hepatectomy. Ethanol-associated inhibition of liver regeneration occurred despite apparently similar serum concentrations of the tumor necrosis factor-inducible cytokine interleukin-6. Treatment with antibodies to tumor necrosis factor 1 hr before partial hepatectomy inhibited post-partial hepatectomy induction of interleukin-6 and liver regeneration in ethanol-fed and pair-fed rats. However, serum interleukin-6 was reduced more in ethanol-fed rats than in control rats (93% vs. 66%; p < 0.05). Antibodies to tumor necrosis factor also inhibited hepatic DNA synthesis more in ethanol-fed rats than in controls (85% vs. 50%; p < 0.05). In ethanol-fed rats, the increased effect of tumor necrosis factor antibody on post-partial hepatectomy DNA synthesis suggests heightened sensitivity of hepatocytes to tumor necrosis factor.(ABSTRACT TRUNCATED AT 250 WORDS)
慢性酒精性肝病的发病机制尚不清楚，但可能反映了对乙醇诱导的肝损伤的伤口愈合反应受损。细胞间通讯，如由细胞因子肿瘤坏死因子介导的通讯，对于肝脏成功再生和从肝损伤中完全恢复是必要的。因此，细胞间再生信号的破坏可能导致慢性酒精性肝病的发病机制。为了验证这一假设，在乙醇喂养的大鼠和等热量维持、配对喂养的对照组中，比较了部分肝切除术后触发的细胞因子和再生反应。为了进一步阐明乙醇对肿瘤坏死因子调节的再生作用的影响，我们在每个喂养组的一些大鼠用肿瘤坏死因子抗体预处理后进行了评估。正如预期的那样，乙醇抑制了部分肝切除术后的DNA合成和肝细胞增殖。尽管肿瘤坏死因子诱导的细胞因子白细胞介素-6的血清浓度明显相似，但乙醇相关的肝再生抑制仍会发生。在部分肝切除术前1小时用肿瘤坏死因子抗体治疗，抑制了乙醇喂养和配对喂养大鼠部分肝切除术后白细胞介素-6的诱导和肝再生。然而，乙醇喂养大鼠的血清白细胞介素-6比对照大鼠降低得更多（93%对66%；p<0.05）。肿瘤坏死因子抗体对乙醇喂养大鼠肝DNA合成的抑制作用也比对对照组更强（85%对50%；p<0.05）。在乙醇喂养的大鼠中，肿瘤坏死因子抗体对部分肝切除术后DNA合成的增强作用表明肝细胞对肿瘤坏死因子的敏感性增加。（摘要截短于250字）
