Palma-Vargas J M, Toledo-Pereyra L, Dean R E, Harkema J M, Dixon R A, Kogan T P
Surgical Research Institute at Borgess Medical Center, Kalamazoo, MI 49001, USA.
J Am Coll Surg. 1997 Oct;185(4):365-72.
The selectin family of adhesion molecules plays a key role in the neutrophil-mediated injury observed after ischemia and reperfusion. In our study, we investigated the effects of TBC-1269, a novel small-molecule, nonoligosaccharide inhibitor of P-, E-, and L-selectin binding, in the liver inflammatory response after 90 minutes of warm ischemia.
Total liver ischemia was produced in Sprague-Dawley rats for 90 minutes using an extracorporeal portosystemic shunt. The animals were divided into five groups including: the sham (group 1), ischemic control (group 2) receiving only the vehicle, and the treated groups receiving TBC-1269 at a dose of 25 mg/kg at different times of administration: 15 minutes before reperfusion (group 3), at reperfusion (group 4), and 15 minutes after reperfusion (group 5). The following indices were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology.
TBC-1269 treated groups experienced a significant increase in survival compared with controls. Best overall survival, 70%, was observed when TBC-1269 (Texas Biotechnology Corporation, Houston, TX) was administered 15 minutes before reperfusion (p < 0.05). This group also showed a marked decrease (p < 0.05) in liver enzyme levels at 6 hours after reperfusion. Neutrophil migration was also significantly ameliorated (81%), as reflected by decreased myeloperoxidase levels. We observed improved histologic damage scores in the treated group compared with controls (p < 0.05).
A small-molecule selectin inhibitor (TBC-1269) had a protective effect in livers subjected to 90 minutes of warm hepatic ischemia and 6 hours of reperfusion by decreasing neutrophil infiltration, migration and subsequent tissue damage. The best protective effect was achieved when the compound was administered 15 minutes before reperfusion. These findings offer a new therapeutic alternative for protection against ischemia and reperfusion injury.
黏附分子选择素家族在缺血再灌注后观察到的中性粒细胞介导的损伤中起关键作用。在我们的研究中，我们研究了新型小分子非寡糖P-、E-和L-选择素结合抑制剂TBC-1269对90分钟热缺血后肝脏炎症反应的影响。
使用体外门体分流术使Sprague-Dawley大鼠全肝缺血90分钟。将动物分为五组，包括：假手术组（第1组）、仅接受赋形剂的缺血对照组（第2组），以及在不同给药时间接受25mg/kg剂量TBC-1269的治疗组：再灌注前15分钟（第3组）、再灌注时（第4组）和再灌注后15分钟（第5组）。分析以下指标：7天生存率、肝损伤检测、作为中性粒细胞浸润指标的肝组织髓过氧化物酶以及肝脏组织学。
与对照组相比，TBC-1269治疗组的生存率显著提高。在再灌注前15分钟给予TBC-1269（德克萨斯生物技术公司，休斯顿，德克萨斯州）时观察到最佳总体生存率，为70%（p<0.05）。该组在再灌注后6小时肝酶水平也显著降低（p<0.05）。中性粒细胞迁移也显著改善（81%），这通过髓过氧化物酶水平降低得以体现。与对照组相比，我们观察到治疗组的组织学损伤评分有所改善（p<0.05）。
小分子选择素抑制剂（TBC-1269）通过减少中性粒细胞浸润、迁移及随后的组织损伤，对经历90分钟热肝缺血和6小时再灌注的肝脏具有保护作用。当在再灌注前15分钟给予该化合物时，可实现最佳保护效果。这些发现为预防缺血再灌注损伤提供了一种新的治疗选择。
