Uchida K, Sakaida I, Hironaka K, Kayano K, Okita K
First Department of Internal Medicine, Yamaguchi University, School of Medicine, Yamaguchi-Prefecture, Japan.
Dig Dis Sci. 2000 Oct;45(10):1996-2001. doi: 10.1023/a:1005698818891.
The aim of the study was to investigate the effect of the immunosuppressant FK 506 (tacrolimus hydrate) on acute liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS). Acute liver injury was induced in male Wistar rats by injecting the animals with P. acnes (10 mg/rat), and administering LPS (10 microg/rat) seven days later. One group was given FK 506 (1 mg/kg) 24 and 2 hr before administration of LPS, and the other group was given the same dose of saline. The 24-hr survival rate, serum alanine aminotransferase (ALT) concentration, and tumor necrosis factor (TNF) -alpha mRNA and protein concentrations in the liver and spleen were then compared. Hepatic macrophages were also isolated from rats seven days after P. acnes injection, LPS, and FK 506 or saline were added to the culture supernatant, and TNF-alpha production was studied. The 24-hr survival rate was 100% in the FK 506-treated group, in contrast with 16.6% in the saline group. Four hours after LPS injection, the serum ALT concentration was 755 +/- 401 in the saline group versus 119 +/- 42 units/ml (P < 0.01) in the FK 506-treated group. The serum TNF-alpha concentration was lower in the FK 506-treated group (1,419 +/- 957 pg/ml) than in the saline group (9205 +/- 2215) (P < 0.01). The mRNA and protein concentrations in the liver and spleen in the two groups did not differ significantly 1 hr after LPS injection but were significantly lower in the FK 506-treated group after 4 hr. FK 506 did not directly inhibit TNF-alpha production by isolated cultured hepatic macrophages. FK 506 is unable to inhibit initial TNF-alpha production by hepatic macrophages (or probably that by splenic macrophages either) stimulated by injection of LPS in P. acnes + LPS-induced acute liver injury. However, the immunosuppressant does limit hepatic damage by inhibiting subsequent aggravation of inflammation by the cytokine network.
本研究旨在探讨免疫抑制剂FK 506（水合他克莫司）对痤疮丙酸杆菌和脂多糖（LPS）诱导的急性肝损伤的影响。通过给雄性Wistar大鼠注射痤疮丙酸杆菌（10 mg/只），并在7天后给予LPS（10 μg/只）来诱导急性肝损伤。一组在给予LPS前24小时和2小时给予FK 506（1 mg/kg），另一组给予相同剂量的生理盐水。然后比较24小时生存率、血清丙氨酸氨基转移酶（ALT）浓度以及肝脏和脾脏中肿瘤坏死因子（TNF）-α mRNA和蛋白浓度。在注射痤疮丙酸杆菌7天后，从大鼠中分离出肝巨噬细胞，将LPS、FK 506或生理盐水添加到培养上清液中，研究TNF-α的产生。FK 506治疗组的24小时生存率为100%，而生理盐水组为16.6%。注射LPS 4小时后，生理盐水组血清ALT浓度为755±401，而FK 506治疗组为119±42单位/毫升（P<0.01）。FK 506治疗组血清TNF-α浓度（1419±957 pg/ml）低于生理盐水组（9205±2215）（P<0.01）。LPS注射1小时后，两组肝脏和脾脏中的mRNA和蛋白浓度无显著差异，但4小时后FK 506治疗组显著降低。FK 506不能直接抑制分离培养的肝巨噬细胞产生TNF-α。在痤疮丙酸杆菌+LPS诱导的急性肝损伤中，FK 506无法抑制LPS注射刺激的肝巨噬细胞（或可能还有脾巨噬细胞）产生初始TNF-α。然而，该免疫抑制剂确实通过抑制细胞因子网络随后的炎症加重来限制肝损伤。
