Article

N-acetylcysteine effects on genotoxic and oxidative stress parameters in cirrhotic rats with hepatopulmonary syndrome.

Laboratory of Experimental Hepatology and Physiology, Porto Alegre Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Basic & Clinical Pharmacology & Toxicology (Impact Factor: 2.18). 05/2008; 102(4):370-6. DOI: 10.1111/j.1742-7843.2007.00181.x
Source: PubMed

ABSTRACT The aim of this study was to evaluate the potential antioxidant effects of N-acetylcysteine in hepatopulmonary syndrome, a complication of cirrhosis, using an experimental model of common bile duct ligation in rats. Male Wistar rats were divided into four experimental groups: CBDL (animals submitted to common bile duct ligation); Sham (animals submitted to simulated common bile duct ligation); Sham + N-acetylcysteine, and CBDL + N-acetylcysteine. N-acetylcysteine (10 mg/kg, intraperitoneally) was administered for 2 weeks starting on day 14 after surgery. Some alterations in the liver integrity were investigated by evaluation of serum enzymes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and arterial blood gases. Lipoperoxidation by thiobarbituric acid-reactive substances assay, superoxide dismutase activity and total nitrates was measured as parameters of oxidative stress, performed on lung homogenates. Micronucleus assay in bone marrow and comet assay in lung, liver and blood were performed to assess the genotoxic effects by oxidative stress. The results showed an improvement in the enzymatic parameters and arterial blood gases, a reduction of lipoperoxidation and in the total nitrates after treatment with N-acetylcysteine. Histological analysis showed vasodilatation in the lung, which was reversed by N-acetylcysteine. Micronuclei frequency and DNA damage in lung and liver were increased in the CBDL group. N-Acetylcysteine caused no genotoxic effect and did not influence the induction of micronucleus in bone marrow and DNA damage in lung and liver. The results suggest protective effects after treatment with N-acetylcysteine in cirrhotic rats with hepatopulmonary syndrome.

0 Bookmarks
 · 
109 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: liver disease, intrapulmonary vascular dilatation and arterial hypoxemia. HPS is reported to be present in 4% to 32% of adult patients with end-stage liver disease and in 9%-20% of children. The pathogenesis of HPS has not been clearly identified. Portal hypertension causes impairment in the perfusion of the bowel and increases the enteral translocation of Gram (-) bacteria and endotoxins. This stimulates the release of vasoactive mediators, such as tumor necrosis factor-alpha, heme oxygenase-derived carbon monoxide and nitric oxide. Genetic alterations have not been associated with this syndrome yet; however, cytokines and chemokines have been suggested to play a role. Recently, it was reported that cumulated monocytes lead to the activation of vascular endothelial growth factor-dependent signaling pathways and pulmonary angiogenesis, which plays an important role in HPS pathogenesis. At present, the most effective and only radical treatment is a liver transplant (LT). Cirrhotic patients who are on the waiting list for an LT have a shorter survival period if they develop HPS. Therefore, it is suggested that all cirrhotic cases should be followed closely for HPS and they should have priority in the waiting list.
    World Journal of Gastroenterology 03/2014; 20(10):2586-2594. · 2.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatopulmonary syndrome (HPS) is a pulmonary complication observed in patients with chronic liver disease and/or portal hypertension, attributable to an intrapulmonary vascular dilatation that induces severe hypoxaemia. Considering the favourable long-term survival of HPS patients as well as the reversal of the syndrome with a functional liver graft, HPS is now an indication for orthotopic liver transplantation (OLT). Consequently, blood gas analysis and imaging techniques should be performed when cirrhotic patients present with shortness of breath as well as when OLT candidates are placed on the transplant waiting list. If the arterial partial pressure of oxygen (PaO2) is more than 10.7 kPa when breathing room air, HPS can be excluded and no other investigation is needed. When the PaO2 when breathing room air is 10.7 kPa or less, contrast-enhanced echocardiography should be performed to exclude pulmonary vascular dilatation. Lung function tests may also help detect additional pulmonary diseases that can contribute to impaired oxygenation. When contrast-enhanced echocardiography is negative, HPS is excluded and no follow-up is needed. When contrast-enhanced echocardiography is positive and PaO2 less than 8 kPa, patients should obtain a severity score that provides them with a reasonable probability of being transplanted within 3 months. In mild-to-moderate HPS (PaO2 8 to 10.6 kPa), periodic follow-up is recommended every 3 months to detect any further deterioration in PaO2. Although no intraoperative deaths have been directly attributed to HPS, oxygenation may worsen immediately following OLT due to volume overload and postoperative infections. Mechanical ventilation is often prolonged with an extended stay in the ICU. A high postoperative mortality (mostly within 6 months) is observed in this group of patients in comparison to non-HPS patients. However, the recovery of an adequate PaO2 within 12 months after OLT explains the similar outcome of HPS and non-HPS patients following OLT over a longer time period.
    European Journal of Anaesthesiology 10/2013; · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Oxidative stress is involved in the hypocontractility of visceral artery to vasoconstrictors and formation of hyperdynamic circulation in cirrhosis with portal hypertension. In the present study, we investigated the effect of reactive oxygen species (ROS) on the mesenteric artery contractility in CCl4-induced cirrhotic rats, and the roles of G protein-coupled receptors (GPCRs) desensitization and RhoA /Rho associated coiled-coil forming protein kinase (ROCK) pathways. Methods: The mesenteric artery contraction to norepinephrine (NE) was determined by vessel perfusion system following treatments with apocynin, tempol or PEG-catalase. The protein expression of α1 adrenergic receptor, β-arrestin-2, ROCK-1, moesin and p-moesin was measured by western blot. The interaction between α1 adrenergic receptor and β-arrestin-2 was assessed by co-immunoprecipitation. Results: Pretreatment with apocynin or PEG-catalase in cirrhotic rats, the hydrogen peroxide level in the mesenteric arteriole was significantly decreased, and the dose-response curve of mesenteric arteriole to NE moved to the left with EC50 decreased. There was no significant change for the expression of α1 adrenergic receptor. However, the protein expression of β-arrestin-2 and its affinity with α1 adrenergic receptor were significantly decreased. The ROCK-1 activity and anti- Y-27632 inhibition in cirrhotic rats increased significantly with the protein expression unchanged. Such effects were not observed in tempol-treated group. Conclusion: The H2O2 decrease in mesenteric artery from rats with cirrhosis resulted in down regulation of the β-arrestin-2 expression and its binding ability with α1 adrenergic receptor, thereby affecting the agonist-induced ROCK activation and improving the contractile response in blood vessels.
    International journal of biological sciences 01/2014; 10(4):386-95. · 3.17 Impact Factor