Primary graft dysfunction is a major complication of orthotopic liver transplantation, and hepatic ischemic reperfusion injury is considered to be its major determinant cause. Although oxygen free radicals play an important role, leukocytes, cytokines, and adhesion molecules also contribute to hepatic ischemic reperfusion injury. Prostaglandin E 1 (PGE 1 ) has been shown to protect against impairment and dysfunction of transplanted livers in various experimental models as well as in clinical liver transplantation. In this study, the role of PGE 1 on leukocyte adherence and transendothelial migration was investigated in cultured human liver vascular endothelial cells (HLVEC). Our results indicated that stimulated, but not resting, leukocytes exhibited high adhesion and transmigration capacity. HLVEC incubated with tumor necrosis factor (TNF) promoted leukocyte adherence and transendothelial migration. PGE 1 inhibited leukocyte adherence to HLVEC when it was preincubated with either HLVEC or leukocytes. Moreover, PGE 1 also suppressed stimulated leukocyte transendothelial migration in a dose-dependent manner. The inhibitory activity of PGE 1 was further investigated on both HLVEC and leukocytes with attention to adhesion molecules. On HLVEC, PGE 1 down-regulated TNF-induced expression of endothelial cell leukocyte adhesion molecule 1 and vascular adhesion molecule 1, but not intercellular adhesion molecule 1. On leukocytes, PGE 1 inhibited expression of CD11a/CD18 and membrane-bound TNF on PHA-stimulated leukocytes. PGE 1 also suppressed TNF release from the stimulated leukocytes. These results indicated that inhibition of leukocyte adherence and transendothelial migration is one of the mechanisms by which PGE 1 protects liver grafts.(HEPATOL-OGY 1998;27:822-828.)
Primary graft dysfunction (PGD) is a major complication of orthotopic liver transplantation. Because hepatic ischemic reperfusion injury is considered to be a major cause of PGD, 1 several prophylactic drugs have been proposed to minimize reperfusion injury. Prostaglandin E (PGE) has been shown to protect against impairment and dysfunction of the transplant liver in various experimental models as well as in clinical liver transplantation. [2][3][4][5] Although it has been shown that PGE 1 has various immune inhibitory activities, the protecting mechanisms for the transplant liver have not been understood completely.
The oxygen free radicals have an important role in hepatic ischemic reperfusion injury because various scavengers of these oxygen radical species have been shown to protect the liver from functional and structural deterioration after reperfusion. [6][7][8] However, the mechanisms of ischemic reperfusion injury are multifactorial and cannot be explained by reactive oxygen intermediates alone. Recent studies indicate that leukocytes (especially polymorphonuclear neutrophils), cytokines, and adhesion molecules also contribute to hepatic ischemic reperfusion injury. [9][10][11][12][13] Leukocyte adhesion and extravasation are associated with the pathogenesis of PGD. Porter et al. reported that infiltration of leukocytes to the portal and sinusoidal endothelial surface was the first histological change, followed by portal edema and cellular invasion of the hepatocyte. 14 Leukocyte sequestration was found in the transplant liver and was considered to be an important pathological feature in ischemic reperfusion injury. [15][16][17][18] The sequestrated and infiltrated leukocytes may promote ischemic reperfusion injury by microvascular obstruction 19 or by release of oxygen free radicals, 20 cytokines, and other cytotoxic factors. 21 Although the mechanisms of leukocyte sequestration and extravasation have not been understood completely, it is well known that this process is related to endothelium activation and the interaction of surface adhesion molecules between leukocytes and endothelial cells. 22 Recent studies suggest that PGE may interfere with the interaction between leukocytes and endothelial cells. In vivo, PGE markedly inhibits monocyte influx into the newly allografted organ in a model of donor-irradiated renal allografts, 23 and in vitro, PGE suppresses T-lymphocyte transendothelial migration. 24 The aim of the present study is to