Preconditioning protects against systemic disorders associated with hepatic ischemia-reperfusion through blockade of tumor necrosis factor–induced P-selectin up-regulation in the rat

• Published in: Hepatology (Baltimore, Md.) Vol. 33; no. 1; pp. 100 - 113
• Main Authors: Peralta, Carmen, Fernández, Leticia, Panés, Julià, Prats, Neus, Sans, Miquel, Piqué, Josep Maria, Gelpı́, Emilio, Roselló-Catafau, Joan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier Inc 2001; W.B. Saunders; Wiley
• Subjects: Animals; Antibodies - pharmacology; Biological and medical sciences; Gastroenterology. Liver. Pancreas. Abdomen; Intercellular Adhesion Molecule-1 - metabolism; Ischemia - complications; Ischemia - metabolism; Ischemia - pathology; Ischemic Preconditioning; Liver - metabolism; Liver - pathology; Liver Circulation; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lung Diseases - prevention & control; Male; Medical sciences; Other diseases. Semiology; P-Selectin - immunology; P-Selectin - metabolism; Rats; Rats, Wistar; Reperfusion Injury - complications; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - physiology; Up-Regulation - drug effects; Rat; Liver; Rodentia; Cardiovascular disease; Hepatic disease; Vascular disease; P Selectin; Vertebrata; Experimental disease; Mammalia; Reperfusion; Cytoprotector; Ischemia; Animal; Digestive diseases; Mechanism of action; Preconditioning; Tumor necrosis factor α
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1053/jhep.2001.20529

Previous studies indicate that ischemic preconditioning protects against lung injury resulting from hepatic ischemia-reperfusion (I/R) through inhibition of tumor necrosis factor (TNF) release from Kupffer cells. The present study investigated whether this effect is limited to the lung or is a generalized systemic response and explores the molecular mechanisms involved. Hepatic I/R led to an increase in neutrophil accumulation in liver, lung, and splanchnic organs. Although preconditioning did not modify neutrophil infiltration in liver during reperfusion, it conferred protection against hepatic injury associated with I/R. In remote organs, preconditioning abrogated the increase in P-selectin up-regulation, preventing neutrophil infiltration and thus reducing the oxidative stress and microvascular disorders following hepatic I/R in these organs. Administration of Abs against P-selectin or TNF previous to ischemia had the same effects as preconditioning. The effects of preconditioning on the blockade of P-selectin up-regulation probably results from inhibition of systemic TNF release from Kupffer cells. Supplementation of TNF abolished the benefits of preconditioning, whereas the injurious effects of TNF were prevented by previous blockade of P-selectin. The results of the present study suggest that ischemic preconditioning protects the liver against I/R injury by a mechanism independent of adhesion molecule expression and neutrophil accumulation. In remote organs, however, hepatic preconditioning prevents inflammatory damage by reducing the systemic TNF release from the liver and thus preventing P-selectin up-regulation. (H EPATOLOGY 2001;33:100-113.)