THE EFFECT OF FR167653 ON PANCREAS ISCHEMIA-REPERFUSION INJURY IN DOGS

Abstract

404 For successful pancreas transplantation, ischemia-reperfusion injury (I/RI) has been a critical problem and the role of cytokines is still unclear. In this study, we evaluated the effect of FR167653 (FR), a newly synthesized, potent suppressant of IL-1 β and TNF α on pancreas. [Methods] In adult mongrel dogs, after complete isolation of the pancreas tail, the splenic vessels were clamped for 90 minutes. During ischemia, the pancreas head was removed. The animals were divided into a control group (n=7) and a FR treatment group (n=7) that received 1 mg/kg/h of FR. We measured s-lipase, amylase, glucose and insulin before ischemia, at 0, 6, 12, 24, 48 and 72 hours after reperfusion. IVGTT was performed at sacrifice and compared to normal. RT-PCR was used for peripheral blood and then expressed as a ratio of IL-1 β/G3PDH at each time. Pancreatic tissue was obtained for histologic examination. Statistical analysis was performed by two-way ANOVA or t-test with p<0.05 for significant difference. [Results] As shown in the figure, s-lipase did not show rapid increase right after reperfusion (282±149 IU/l vs. normal 235±71), but increased markedly thereafter (1095±146 at 72 hrs) in control group. In FR group, however, lipase was significantly lower than control at all times (375±158 at 72 hrs, p=0.021). Similarly s-amylase was suppressed in FR group, but without significant difference. ΔIRI/ΔBS at 5 mins of IVGTT showed an impaired response in control (0.074±0.024) as well as FR group (0.041±0.027), compared to normal (0.147±0.023, N.S.). IL-1 β/G3PDH increased at 24 hours then gradually decreased in the control (0.342±0.047 at 24 hrs), but remained low in FR group (0.135±0.046 at 24 hrs, p=0.028). Histologic examination revealed moderate pancreatitis with edema, cell infiltration and scattered hemorrhage in the control group, and less damage in the FR group.Figure[Conclusions] There is a marked impairment of pancreas exocrine function after reperfusion. FR ameliorates I/RI of the pancreas by inhibition of proinflammatory cytokine production, which would be beneficial for pancreas preservation and transplantation.