LPS Pretreatment Protects from Hepatic Ischemia/Reperfusion

Abstract

In vivo administration of nonlethal doses of lipopolysaccharide (LPS) to rodents can result in protection from subsequent lethal doses of endotoxin or LPS. We have previously demonstrated that hepatic ischemia/reperfusion (I/R) results in a TNF-dependent lung and liver injury and we postulated that pretreatment with sublethal concentrations of LPS prior to hepatic I/R could be protective from this injury. To test this hypothesis, five groups of rats were studied. LPS-I/R received 25 [mu]g of LPS iv 24 hr prior to I/R, VEH-I/R received an equivalent volume of vehicle iv 24 hr prior to I/R, LPS-LPS received 25 [mu]g of LPS iv 24 hr prior to sham laparotomy at which time an additional 25 [mu]g of LPS was given iv, VEH-LPS received an equivalent volume of vehicle 24 hr prior to sham laparotomy and 25 [mu]g of LPS iv immediately prior to sham laparotomy, and SHAM consisted of sham-operated control animals. Peak plasma tumor necrosis factor-[alpha] (TNF) levels occurred between 30 and 150 min of reperfusion: LPS-I/R 778 +/- 150 pg/ml (n = 5), VEH-I/R = 145 +/- 46 pg/ml (n = 5), LPS-LPS = 970 +/- 716 pg/ml (n = 4), VEH-LPS = 15,949 +/- 10,937 (n = 5), and SHAM = 3 +/- 1 (n = 5). As previously demonstrated by other investigators, pretreatment with LPS decreases TNF release in response to a second dose of LPS; however, TNF release was increased following hepatic I/R in those animals pretreated with LPS (LPS-I/R vs VEH-I/R, P = 0.014). Pulmonary injury was assessed by total protein and cell counts in bronchoalveolar lavage (BAL) fluid. Total protein concentration in BAL fluid from LPS-I/R 59.48 +/- 14.87 [mu]g/ml (n = 11) and from VEH-I/R = 239.41 +/- 60.12 [mu]g/ml (n = 16) (P n = 7), 81.71 +/- 1 O. 14 [mu]g/m] (n = 7), and 33.02 +/- 12.22 [mu]g/ml (n = 8), respectively, and were not significantly different from each other. BAL fluid cell counts paralleled protein levels in each group. These data suggest that pretreatment with LPS increases TNF release in response to I/R, but protects from the subsequent pulmonary injury. In addition, liver injury in this model was assessed by quantitation of serum AST. There was no evidence of a difference in the liver injury which followed hepatic ischemia/reperfusion in animals which were pretreated with LPS before hepatic I/R.