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

Abstract

Hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveoloarterial oxygen difference (AaPO(2)). 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). AaPO(2) and cerebral uptake of intravenous (99m)Tc-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.

Lung and Liver Changes Due to the Induction of Cirrhosis in Two Experimental Models

“…When we evaluated lipid peroxidation in the two models of cirrhosis, animals in the EX group had significantly higher values compared to those in the CO group, and the level of TBARS and QL were elevated in the lung and liver in both groups. This overproduction of ROS might occur in several pathophysiological situations and may explain the finding that in our study, the levels of TBARS and QL were high (22,23) . Physiological defense mechanisms are effective in preventing or counteracting the damage caused by free radicals, which can include a set of endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx).…”

“…PPH patients exhibit arterial hypoxemia and arterial oxygenation that is significantly worse when comparing liver transplantation candidates with normal vascular resistance as determined by echocardiography Doppler (16) . In the BDL model, hypoxemia may be associated with bacterial translocation occurring in 45%-75% of cirrhotic animals whereby the induced hepatocellular damage prevents adequate blood filtration and promotes the development of portosystemic shunts; this phenomenon dramatically decreases the phagocytic ability of the liver, and it also allows the entry of bacteria and endotoxins into the lung circulation (23) . Furthermore, studies have reported arterial hypoxemia in BDL animals, which contributes to a reduction in the values of PaO 2 due to increased volume of lung shunt (32) .…”

“…Nitric oxide is a potent vasodilator that promotes dilation of intrapulmonary vessels, leading to hypoxemia. Nitric oxide may also be involved in the mechanisms that cause an imbalance between the antioxidants and oxidants (23) . Regarding photomicrographs of the lung tissue, the BDL model caused an increase in diameter of arterioles of the lung tissue.…”

Modelos experimentais para avaliação das alterações pulmonares na síndrome hepatopulmonar

“…During phagocytosis, the activation of numerous macrophages results in the secretion of products such as cytokines and nitric oxide into the extracellular medium, nitric oxide being a potent vasodilator and also being involved in mechanisms of imbalance between the antioxidant and oxidative systems. (24) Nitric oxide functions as a molecular signaler (mediating vasodilatation when produced at low concentrations by nitric oxide synthase in endothelial vascular cells) and as a highly toxic oxidant source (when produced at high concentration by nitric oxide synthase in macrophages in the inflammatory process), thereby promoting intrapulmonary vasodilatation followed by hypoxemia. (25) Many authors have reported that, in the presence of cirrhosis, there is a considerable increase of lipoperoxidation due to the formation of reac-…”

Hepatopulmonary syndrome: More than just a matter of tone?

“…9 During the progression of HPS, increased tumor necrosis factor alpha production associated with bacterial translocation contributes to intravascular macrophage accumulation and inducible nitric oxide synthase expression. 10 Recently, increased intravascular macrophage heme oxygenase-1 expression and carbon monoxide overproduction have been identified after common bile duct ligation and also appear to contribute to changes in the microvasculature. 11 In human HPS, pulmonary NO overproduction, as assessed by exhaled NO levels has also been found.…”