The Primary Study Of Signal Pathways Of Isografts And Mechanisms Of Lung Injury In Early Phase Of Small-for-size Liver Transplantation In Rats

Part I The Primary Study of Signal Pathways of Isografts in Early Phaseof Small-for-size Liver Transplantation in RatsIntroductionLiver transplantation has been widely used as the therapy for patients with end-stage liver disease. However, the shortage of donor organs limits the application of liver transplantation. In last decade, some methods to expand the donor pool such as split liver transplantation (SLT) , reduced size liver transplantation (RSLT) and living donor liver transplantation (LDLT) were widely used and made a rapid progress. Living donor liver transplantation, which originated in the early 1990s and firstly applied in pediatric liver transplantation, has now been applied largely to adult liver transplantation. Compared with whole graft liver transplantation, LDLT suffered more risks and injuries with a high mortality and problem related to "small-for-size grafts" have gradually come to light. "Small-for-size syndrome (SFSS)", such as delayed poor synthetic function, poor bile production, intractable ascites, and prolonged cholestasis, leaded to septic complications and higher mortality. Primary graft insufficient or nonfunction is a major problem occurred in livertransplantation, especially in small-for-size liver transplantation. Apart from the common I/R injury that occurred in liver transplantation using whole grafts, the small-for-size grafts suffer mechanical injury related to hemodynamic force. Previous studies have demonstrated that transient portal hypertension and subsequent microcirculation disturbance are the major problems occurred in the early phase of small-for-size liver transplantation. However, the molecular mechanism of small-for-size graft injuries remains unclear. Man et al have demonstrated that the up-regulation of intragraft vasoconstriction genes accompanied by early over-expression of adhesion molecules and apoptotic signals, as well as down-regulation of heat shock protein-70 (Hsp-70) and HO-1 in small-for-size grafts may be related to sinusoidal injury leading to graft damage in liver transplantation. Liang's study has also revealed that small-for-size graft injury is related to early over-expression of early growth response factor-1 (Egr-1) associated with up-regulation of endothelin-1 (ET-1) and down-regulation of Hsps and A20. Low-dose FK409 rescues small-for-size grafts in liver transplantation by attenuation of portal hypertension and amelioration of acute phase inflammatory response by down-regulation of Egr-1 and induction of Hsps.Ischemia/reperfusion (I/R) injury is a multifactorial process that affects graft function after liver transplantation, which is characterized by activation of Kuppfer cells, acute phase inflammatory response, microcirculatory disturbances and apoptosis of sinusoidal endothelial cells (SEC) and hepatocytes. Apoptosis, also called programmed cell death, is an active process of cell death during which the affected cell, either in response to physiological or pathological conditions and plays a key role in maintenance of dynamic steady state of internal environment. The activation and execution of apoptosis is regulated by complex molecular machinery. Recent studies have demonstrated that apoptosis was one of the most important pathologic characters and involved in hepatic I/R injury. Apoptosis of sinusoidal endothelial cells (SEC) and hepatocytes has been observed during the early phase of I/R in the rat liver and is considered to be a criticalmechanism of preservation injury in rat liver transplantation. Therefore, the dynamic balance of cell survival and apoptosis is critical in determining the fate of hepatocytes and SEC subsequent to reperfusional injury. The balance is controlled through pro-apoptotic and anti-apoptotic genes and their protein products including the upstream signal pathways.The signaling pathways play important roles in the signals transduction from the cell membrane to the nuclear transcriptional factors in the setting of cellular stress. Recent studies have demonstrated that both aggravating signal pathways (relate...