Kupffer cells and 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 hepatocellular HO-1 gene expression in a rat model of hemorrhage and resuscitation. Male Sprague-Dawley rats (n = 6-10/group) were anesthetized (pentobarbital, 50 mg/kg intraperitonal) and subjected to hemorrhagic shock (mean arterial 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, Kupffer cell blockade [gadolinium chloride (GdCl3); 10 mg/kg; 24 h prior to hemorrhage or dichloromethylene diphosphonate (Cl2MDP); 1 mg/kg; 2 days prior to hemorrhage], or neutrophil depletion (vinblastine, 0.5 mg/kg, 5 days prior to hemorrhage) on induction of the HO-1 gene was assessed at 5 h of resuscitation, i.e., the time point of maximal induction. Kupffer cell blockade and antioxidants abolished HO-1 mRNA and protein induction after hemorrhage, while neutrophil depletion failed to affect hepatocellular HO-1 gene expression. In addition, Kupffer cell blockade aggravated hepatocellular injury. N-formyl-methionine-leucyl-phenylalanin (fMLP) induced a substantial influx of neutrophils into the liver but failed to induce hepatocellular HO-1 mRNA expression. These data suggest that Kupffer cells but not neutrophils induce an adaptive hepatocellular stress response after hemorrhage and resuscitation. Oxygen-free radicals released by Kupffer cells may serve as paracrine regulators of a hepatocellular stress gene which is necessary to maintain liver blood flow and integrity under stress conditions.
Paxian
M
M
Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany.
Rensing
H
H
Rickauer
A
A
Schönhofen
S
S
Schmeck
J
J
Pannen
B H
BH
Bauer
I
I
Bauer
M
M
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D005682:Gadolinium / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D022781:Hepatocytes / Q000201:enzymology*; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D013997:Time Factors; D014747:Vinblastine / Q000494:pharmacology
D000975:Antioxidants; D002839:Chromans; D004002:Clodronic Acid; D014747:Vinblastine; D005682:Gadolinium; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D003676:Deferoxamine; C038958:gadolinium chloride; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D000111:Acetylcysteine