Summary
The clinical significance of a myeloperoxidase (MPO) gene polymorphism and inducible nitric oxide synthase (iNOS) expression in cirrhotic patients with hepatopulmonary syndrome (HPS) was explored. Enrolled subjects were divided into three groups according to their disease/health conditions: the HPS group (cirrhotic patients with HPS; n=63), the non-HPS group (cirrhotic patients without HPS; n=182), and the control group (healthy subjects without liver disease; n=35). The distribution of the MPO −463 G/A genotype and its relationship with iNOS expression in a typical cell block from ascitic fluid were detected by immunohistochemistry and polymerase chain reaction-restricted fragment length polymorphism analysis (PCR-RFLP). In the HPS group, the partial pressure of oxygen in blood and ascitic fluid was significantly decreased (8.95±1.58 kPa and 6.81±0.95 kPa, respectively; both P<0.01), while the partial pressure of carbon dioxide significantly increased (4.62±0.20 kPa and 5.92±0.45 kPa, respectively; P<0.01). MPO and iNOS levels were significantly increased in the HPS group as compared with the non-HPS group. These increases were even more remarkable in ascitic fluid (41.36±11.62 and 13.23±4.81 μg/L; 10.27± 3.20 and 4.95±1.12 μg/L) than in blood (16.66±5.24 and 4.87±1.73 μg/L; 5.79±2.31 and 2.35±0.84 μg/L). The distribution of the MPO genotypes GG, GA, and AA were 76.2%, 22.2% and 1.6% in the HPS group, and 57.7%, 37.9% and 4.4% in the non-HPS group (P<0.05). The expression of iNOS was significantly higher in patients with the G alleles (G/G and G/A) (61.54%, 48/78) than in patients with A alleles (G/A and A/A) (38.46%, 30/78) (P<0.01). It was suggested that the expression levels of iNOS and MPO were correlated with HPS-induced hypoxemia. The MPO-463 G/A mutation might be a protective factor that prevents the development of HPS. The MPO might be involved in the regulation of iNOS expression. In humans, MPO pathways, the iNOS/NO system, and their interaction might have an impact on the occurrence and development of HPS.
Similar content being viewed by others
References
Schenk P, Fuhrman V, Madl C, et al. Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences. Gut, 2002,51(6):853–859
Aller R, Moreira V, Boixeda D, et al. Diagnosis of hepatopulmonary syndrome with contrast transthoracic echocardiography and histological confirmation. Liver, 1998, 18(5):285–287
Kikuchi H, Ohkohchi N, Orii T, et al. Living-related liver transplantation in patients with hepatopulmonary syndrome disease. Transplant Proc, 2000,32(7):2177–2178
Fallon MB. Mechanisms of pulmonary vascular complications of liver disease: hepatopulmonary syndrome. J Clin Gastroenterol, 2005,39(Suppl):S138–S142
Zhang XJ, Katsuta Y, Akimoto T, et al. Intrapulmonary vascular dilatation and nitric oxide in hypoxemic rats with chronic bile duct ligation. J Hepatol, 2003,39(5):724–730
Zhu YY, Jing BW, Lou YH. Experimental study of early lung injury caused by abdominal infection in rats. Zhongguo Jijiu Yixue Zazhi (Chinese), 2000,20(3):131–133
Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med, 1998,157(5):1666–1680
Yan L. Expression of nitric oxide synthase in human phagocytes up-regulates the production of TNF2α. Xibao Yu Fenzi Mianyixue Zazhi (Chinese), 1997,13(1):9–12
Ye RG, Lu ZY. Medicine (Chinese). 6th ed. Beijing: People’s Medical Publishing House, 2004,440–449.
Rodriguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N Engl J Med, 2008,358(22):2378–2387
Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16 (INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer, 2001,92(2):276–284
Krowka MJ, Cortese DA. Hepatopulmonary syndrome: current concepts in diagnostic and therapeutic considerations. Chest, 1994,105(5):1528–1537
Narumiya S, Ishizaki T, Watanabe N. Rho effectors and reorganization of actin cytoskeleton. FEBS Lett, 1997, 410(1):68–72
Fanning AS, Mitic LL, Anderson JM. Transmembrane proteins in the tight junction barrier. J Am Soc Nephrol, 1999,10(6):1337–1345
Brain JD, Molina RM, DeCamp MM, et al. Pulmonary intravascular macrophages: their contribution to the mononuclear phagocyte system in 13 species. Am J Physiol, 1999,276(1): L146–154
Colgan SP, Dzus AL, Parkos CA. Epithelial exposure to hypoxia modulates neutrophil transepithelial migration. J Exp Med, 1996,184(3):1003–1015
Li X, Han DW, Zhao LF. Effect of glycine on the expression of peroxisome proliferators-activated receptorα in the rat nonalchoholic fatty liver. Zhongguo Bingli Shengli Zazhi (Chinese), 2006,22(9):1829–1832
Bailey MT, Engler H, Sheridan JF. Stress induces the translocation of cutaneous and gastrointestinal microflora to secondary lymphoid organs of C57BL/6 mice. J Neuroimmunol, 2006,171(1–2):29–37
Cutrn JC, Perrelli MG, Canvalieri B, et al. Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning. Free Radical Bio & Med, 2002,33(9):1200–1208
Fondevila C, Busuttil RW, Kupiec-Weglinski JW. Hepatic ischemia/reperfusion injury — a fresh look. EXP Mol Pathol, 2003,74(2):86–93
Zhang C, Reiter C, Eiserieh JP, et al. L-Arginine chlorination products inhibit endothelial nitric oxide production. J Biol Chem, 2001,276(29):27 159–27 165
Auchere F, Capeillere-Blandin C. NADPH as a co-substrate for studies of the chlorinating activity of myeloperoxidase. Biochem J, 1999,343(pt3):603–613
Schroeder RA, Ewing CA, Sitamann JV, et al. Pulmonary expression of iNOS and HO-1 protein is upregulated in a rat model of prehepatic portal hypertension. Dig Dis Sci, 2000,45(12):2405–2410
Rolla G, Brussino L, Colagrande P, et al. Exhaled nitric oxide and impaired oxygenation in cirrhotic patients before and after liver transplantation. Ann Intern Med, 1998, 129(5):375–378
Zhang XJ, Katsuta Y, Akimoto T, et al. Intrapulmonary vascular dilatation and nitric oxide in hypoxemic rats with chronic bile duct ligation. J Hepatol, 2003,39(5):724–730
Halpern MD, Holubec H, Dominguez JA, et al. Hepatic inflammatory mediators contribute to intestinal damage in necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol, 2003,284(4):695–702
Alizadeh AH, Fatemi SR, Mirzaee V, et al. Clinical features of hepatopulmonary syndrome in cirrhotic patients. World J Gastroenterol, 2006,12(12):1954–1956
Krowka MS, Wiseman GA, Burnett OL, et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO2 response to 100% oxygen, and brain uptake after 99mTcMAA lung scanning. Chest, 2000,118(3):615–624
Austin GE, Lam L, Zaki SR, et al. Sequence comparison of putative regulatory DNA of the 5′ flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells. Leukemia, 1993,7(9):1445–1450
Piedrafita FJ, Molander RB, Vansant G, et al. An Alu element in the myeloperoxidase promoter contains a composite SP 1-thyroid hormone-retinoic acid response element. J Biol Chem, 1996,271(24):14 412–14 420
Eiserich JP, Baldus S, Bronnan ML, et al. Myeloporoxidase, a leukocyte-derived vascular NO oxidase. Science, 2002,296(5577):2391–2394
Abu-Soud HM, Khassawneh MY, Sohn JT, et al. Peroxidases inhibits nitric oxide (NO) dependent bronchodilation: development of a model describing NO-peroxidase interactions. Biochemistry, 2001,40(39):11 866–11 875
Zhang C, Patel R, Eiserich JP, et al. Endothelial dysfunction is induced by proinflammatory oxidant hypochlorous acid. Am J Physiol Heart Circ Physiol, 2001,281(4): H1469–H1475
Ma H, Zhao X, Wang YY, et al. Research on hypoxia-inducible factor-1α and inducible nitric oxide synthase levels and portal hemodynamics in patients with hepatopulmonary syndrome. Zhongguo Jiceng Yiyao Zazhi (Chinese), 2010,2(17):145–148
Author information
Authors and Affiliations
Corresponding author
Additional information
This project was supported by a grant from Heilongjiang Provincial Science and Technology Breakthrough Project Foundation (No. GB07C32506).
Rights and permissions
About this article
Cite this article
Wang, Y., Wang, W., Zhang, Y. et al. Clinical significance of a myeloperoxidase gene polymorphism and inducible nitric oxide synthase expression in cirrhotic patients with hepatopulmonary syndrome. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 30, 437–442 (2010). https://doi.org/10.1007/s11596-010-0445-1
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-010-0445-1