Kupffer cells end neutrophils as paracrine regulators of the heme oxygenase-1 gene in hepatocytes after hemorrhagic shock

Heme oxygenase (HO) plays a pivotal role for the maintenance of liver blood flow and hepatocellular integrity after hemorrhagic shock. We investigated the role of Kupffer cells and neutrophils as paracrine modulators of hepat ocellular HO-1. gene expression in a rat model of hemorrhage and resuscitat ion. Male Sprague-Dawley rats (n = 6-10/group) were anesthetized (pentobarb ital, 50 mg/kg intraperitonal) and subjected to hemorrhagic shock (mean art erial blood pressure: 35 mmHg for 60 min) or a sham protocol. Based on the time course of HO-1 gene expression, the effect of various antioxidants, Ku pffer cell blockade [gadolinium chloride (GdCl3); 10 mg/kg; 24 h prior to h emorrhage or dichloromethylene diphosphonate (Cl2MDP); 1 mg/kg; 2 days prio r to hemorrhage], or neutrophil depletion (vinblastine, 0.5 mg/kg, 5 days p rior to hemorrhage) on induction of the HO-1 gene was assessed at 5 h of re suscitation, i.e., the time point of maximal induction. Kupffer cell blocka de and antioxidants abolished HO-1 mRNA and protein induction after hemorrh age, while neutrophil depletion failed to affect hepatocellular HO-1 gene e xpression. In addition, Kupffer cell blockade aggravated hepatocellular inj ury. N-formyl-methionine-leucyl-phenylalanin (fMLP) induced a substantial i nflux of neutrophils into the liver but failed to induce hepatocellular HO- 1 mRNA expression. These data suggest that Kupffer cells but not neutrophil s induce an adaptive hepatocellular stress response after hemorrhage and re suscitation. Oxygen-free radicals released by Kupffer cells may serve as pa racrine regulators of a hepatocellular stress gene which is necessary to ma intain liver blood flow and integrity under stress conditions.