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Prevention of Gram-Negative Translocation Reduces the Severity of Hepatopulmonary Syndrome

Laboratoire de Chirurgie Expérimentale-UPRES, Centre Chirurgical Marie Lannelongue, Université Paris Sud, Paris; and Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U-481, Hôpital Beaujon, Clichy, France

Correspondence and requests for reprints should be addressed to P. Hervé, M.D., Centre Chirurgical Marie Lannelongue, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France. E-mail: pherve{at}ccml.com

Hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveoloarterial oxygen difference (AaPO₂). These abnormalities are related to augmented pulmonary nitric oxide (NO) production, dependent primarily on increases in the expression and activity of inducible NO-synthase (iNOS) within pulmonary intravascular macrophages and, to a lesser extent, of endothelial NOS (eNOS). Production of iNOS by pulmonary intravascular macrophages might be related to translocated gut bacteria present in the pulmonary circulation. To test this hypothesis, we determined whether macrophage sequestration, lung iNOS expression and activity, and HPS severity were decreased after norfloxacin was given for 5 weeks to prevent Gram-negative bacterial translocation in rats with common bile duct ligation–induced cirrhosis. Norfloxacin decreased the incidence of Gram-negative translocation from 70 to 0% and the percentage of pulmonary microvessels containing more than 10 macrophages from 52 ± 7 to 21 ± 8% (p < 0.01). AaPO₂ and cerebral uptake of intravenous ^99mTc-labeled albumin macroaggregates (reflecting intrapulmonary vascular dilatations) were intermediate to those of untreated cirrhotic and sham-operated rats. The activity and expression of lung iNOS, but not eNOS, were reduced to normal. Norfloxacin may reduce HPS severity by inhibiting Gram-negative bacterial translocation, thereby decreasing NO production by pulmonary intravascular macrophages. Bacterial translocation may be the key to the pathogenesis of HPS.

Key Words: experimental cirrhosis • hepatopulmonary syndrome • macrophage • bacterial translocation • nitric oxide synthase

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