Xenos E S, Stevens R B, Sutherland D E, Lokeh A, Ansite J D, Casanova D, Gores P F, Platt J L
Department of Surgery, Syracuse Medical Center, New York State University.
Transplantation. 1994 Apr 27;57(8):1208-12. doi: 10.1097/00007890-199404270-00012.
Products of inflammation, such as interleukin-1 beta (IL-1 beta) and nitric oxide (NO), may impair early function of pancreatic islet grafts. In in vitro studies, freshly isolated rat islets of Langerhans cultured for 24 hr (10 islets/well) in the presence of 20 IU/ml of IL-1 beta released 57% less insulin (mean +/- S.E. of 151 +/- 61 microU) on the average than control (385 +/- 89 microU) cultures (n = 9, P = 0.08). Nitrite levels in the medium (indirect measure of NO) after islets were cultured for a 24-hr period were nearly 3-fold greater in IL-1 beta-exposed islets than control islet cultures (5.8 +/- 1.0 microM vs. 2.2 +/- 0.3 microM, P = 0.03). Production of nitrite by islet cells in the presence of IL-1 beta was inhibited in cultures also containing 2 mM L-NG-monomethyl-Arginine (L-NMMA) (3.4 +/- 0.4 microM, n = 9, P = 0.09 vs. control). When islets were maintained for 1 hr in 30 mg/dl glucose followed by 300 mg/dl for 1 hr, insulin release (stimulated) increased 6-fold (from 7 +/- 2 to 45 +/- 11 microU) in control cultures but only 3-fold (from 4 +/- 2 to 12 +/- 4 microU) in IL-1 beta-exposed cultures (n = 9, P = .01). Addition of 2 mM L-NMMA to islet cultures in the presence of IL-1 beta (20 IU/ml) (n = 9) restored insulin release to normal (from 6 +/- 2 to 38 +/- 9 microU, P > or = 0.6), suggesting that NO mediates the inhibitory effect of IL-1 beta on beta-cell function. In in vivo studies, rats with streptozotocin-induced diabetes (blood glucose > 400 mg/dl) received minimal (750 hand-picked islets) intraportal beta cell mass isografts with (n = 5) or without (n = 9) treatment with 100 mg/7 days of L-NMMA from 3 days before transplantation to 4 days after transplantation (POD -3 to +4). L-NMMA-treated rats became euglycemic (glucose < 200 mg/dl) earlier than nontreated rats (mean +/- SD of 6.4 +/- 2.5 vs. 16.7 +/- 4.7 days posttransplant, P = 0.001). These findings support the hypothesis that NO is a mediator of beta cell dysfunction after intraportal transplantation of freshly isolated islets of Langerhans.
炎症产物，如白细胞介素-1β（IL-1β）和一氧化氮（NO），可能会损害胰岛移植的早期功能。在体外研究中，新鲜分离的大鼠胰岛在20 IU/ml IL-1β存在下培养24小时（每孔10个胰岛），平均释放的胰岛素比对照培养物（385±89微单位）少57%（平均±标准误为151±61微单位）（n = 9，P = 0.08）。胰岛培养24小时后，培养基中亚硝酸盐水平（NO的间接测量指标）在暴露于IL-1β的胰岛中比对照胰岛培养物高出近3倍（5.8±1.0微摩尔/升对2.2±0.3微摩尔/升，P = 0.03）。在同时含有2 mM L-NG-单甲基精氨酸（L-NMMA）的培养物中，IL-1β存在下胰岛细胞产生亚硝酸盐的情况受到抑制（3.4±0.4微摩尔/升，n = 9，与对照相比P = 0.09）。当胰岛先在30 mg/dl葡萄糖中维持1小时，然后在300 mg/dl葡萄糖中维持1小时时，对照培养物中胰岛素释放（刺激后）增加了6倍（从7±2微单位增加到45±11微单位），但在暴露于IL-1β的培养物中仅增加了3倍（从4±2微单位增加到12±4微单位）（n = 9，P = 0.01）。在IL-1β（20 IU/ml）存在下向胰岛培养物中添加2 mM L-NMMA（n = 9）可使胰岛素释放恢复正常（从6±2微单位增加到38±9微单位，P≥0.6），这表明NO介导了IL-1β对β细胞功能的抑制作用。在体内研究中，链脲佐菌素诱导的糖尿病大鼠（血糖>400 mg/dl）在移植前3天至移植后4天（移植后第-3天至+4天）接受了最小量（750个精心挑选的胰岛）门静脉内β细胞团同种异体移植，其中一组（n = 5）接受100 mg/7天的L-NMMA治疗，另一组（n = 9）未接受治疗。接受L-NMMA治疗的大鼠比未治疗的大鼠更早实现血糖正常（移植后平均±标准差为6.4±2.5天对16.7±4.7天，P = 0.001）。这些发现支持了以下假设：NO是新鲜分离的大鼠胰岛门静脉内移植后β细胞功能障碍的介导因子。
