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Published in: Pediatric Surgery International 9/2010

01-09-2010 | Original Article

NF-κB related abnormal hyper-expression of iNOS and NO correlates with the inflammation procedure in biliary atresia livers

Authors: Lei Huang, Xin-Min Si, Jie-Xiong Feng

Published in: Pediatric Surgery International | Issue 9/2010

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Abstract

Objective

To study the expression of inducible nitric oxide synthase (iNOS) and its related regulators in biliary atresia (BA) livers and exlpore their relationships with the inflammation pathway in BA livers.

Method

The iNOS expression in livers of 38 cases of BA children, 15 cases of neonatal cholestasis (NC) children, and 18 cases of normal control were, respectively, examined and total nitric oxide (NO) metabolites concentration of all samples were calculated by a colorimetric method based on Griess reaction. The TdT-mediated dupt biotin nick end labeling (TUNEL) method was used to label the apoptotic bile duct epithelial cells and hepatocytes. The western blotting and immunohistochemistry methods to semi-quantitatively analyze the nuclear factor-κB (NF-κB) expression of each group were also used.

Results

The iNOS expression intensity and total NO metabolites concentration of BA group (0.30 ± 0.08, 90.40 ± 12.46 μmol/L) were significantly higher than those of NC and normal control groups, P < 0.01. Correlation analysis showed a strong positive correlation between the serum AST level (152.76 ± 29.59 U/L) and total NO metabolites concentration in BA group. Compared with the NC (32.47 ± 5.55) and normal control (20.72 ± 5.63) groups, a significantly higher apoptosis rate of intrahepatic bile duct epithelial cells was found in BA group (54.00 ± 11.67) that tightly correlated with the iNOS intensity (r = 0.99, P < 0.01). The NF-κB intensity of BA group was also significantly higher than that of NC and normal control groups and had a strong positive correlation with the iNOS intensity (r = 0.97, P < 0.01).

Conclusion

The abnormal hyper-expression of iNOS may play an important role in mediating the inflammation procedure in BA livers. This change perhaps has some relationship with the high expression of NF-κB and NO. These regulators can up-regulate the apoptosis of bile duct epithelial cells in BA livers and cause the damage to liver tissues.
Literature
1.
2.
go back to reference Mack CL (2007) The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis 27:233–242CrossRefPubMed Mack CL (2007) The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis 27:233–242CrossRefPubMed
3.
go back to reference Roach JP, Bruny JL (2008) Advances in the understanding and treatment of biliary atresia. Curr Opin Pediatr 20:315–319CrossRefPubMed Roach JP, Bruny JL (2008) Advances in the understanding and treatment of biliary atresia. Curr Opin Pediatr 20:315–319CrossRefPubMed
4.
go back to reference Mack CL, Sokol RJ (2005) Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 57:87–94CrossRef Mack CL, Sokol RJ (2005) Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 57:87–94CrossRef
5.
go back to reference Hamada T, Duarte S, Tsuchihashi S et al (2009) Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury. Am J Pathol 174:2265–2277CrossRefPubMed Hamada T, Duarte S, Tsuchihashi S et al (2009) Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury. Am J Pathol 174:2265–2277CrossRefPubMed
6.
go back to reference Farombi EO, Shrotriya S, Surh YJ (2009) Kolaviron inhibits dimethyl nitrosamine-induced liver injury by suppressing COX-2 and iNOS expression via NF-κB and AP-1. Life Sci 30:149–155CrossRef Farombi EO, Shrotriya S, Surh YJ (2009) Kolaviron inhibits dimethyl nitrosamine-induced liver injury by suppressing COX-2 and iNOS expression via NF-κB and AP-1. Life Sci 30:149–155CrossRef
8.
9.
go back to reference Mack CL, Tucker RM, Sokol RJ et al (2004) Biliary atresia is associated with CD4 + Th1 cell mediated inflammation within portal tracts. Pediatr Res 56:79–87CrossRefPubMed Mack CL, Tucker RM, Sokol RJ et al (2004) Biliary atresia is associated with CD4 + Th1 cell mediated inflammation within portal tracts. Pediatr Res 56:79–87CrossRefPubMed
10.
go back to reference Lange M, Enkhbaatar P, Nakano Y et al (2009) Role of nitric oxide in shock: the large animal perspective. Front Biosci 14:1979–1989CrossRefPubMed Lange M, Enkhbaatar P, Nakano Y et al (2009) Role of nitric oxide in shock: the large animal perspective. Front Biosci 14:1979–1989CrossRefPubMed
11.
go back to reference Rajapakse NW, Mattson DL (2009) Role of L-arginine in nitric oxide production in heASTh and hypertension. Clin Exp Pharmacol Physiol 36:249–255CrossRefPubMed Rajapakse NW, Mattson DL (2009) Role of L-arginine in nitric oxide production in heASTh and hypertension. Clin Exp Pharmacol Physiol 36:249–255CrossRefPubMed
12.
go back to reference Okhotin VE, Shuklin AV (2006) Significance of neuronal, endothelial and inducible NO-synthase isoforms in the cardiac muscle histophysiology. Morfologiia 129:7–17PubMed Okhotin VE, Shuklin AV (2006) Significance of neuronal, endothelial and inducible NO-synthase isoforms in the cardiac muscle histophysiology. Morfologiia 129:7–17PubMed
13.
go back to reference Ebrahimi F, Tavakoli S, Hajrasouliha AR et al (2006) Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats. Fundam Clin Pharmacol 20:461–471CrossRefPubMed Ebrahimi F, Tavakoli S, Hajrasouliha AR et al (2006) Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats. Fundam Clin Pharmacol 20:461–471CrossRefPubMed
14.
go back to reference Hokari A, Zeniya M, Esumi H et al (2002) Detection of serum nitrite and nitrate in primary biliary cirrhosis: possible role of nitric oxide in bile duct injury. J Gastroenterol Hepatol 17:308–315CrossRefPubMed Hokari A, Zeniya M, Esumi H et al (2002) Detection of serum nitrite and nitrate in primary biliary cirrhosis: possible role of nitric oxide in bile duct injury. J Gastroenterol Hepatol 17:308–315CrossRefPubMed
15.
go back to reference Chongsrisawat V, Chatchatee P, Samransamruajkit R et al (2003) Plasma endothelin-1 levels in patients with biliary atresia: possible role in development of portal hypertension. Pediatr Surg Int 19:478–481CrossRefPubMed Chongsrisawat V, Chatchatee P, Samransamruajkit R et al (2003) Plasma endothelin-1 levels in patients with biliary atresia: possible role in development of portal hypertension. Pediatr Surg Int 19:478–481CrossRefPubMed
16.
go back to reference Chen T, Zamora R, Zuckerbraun B et al (2003) Role of nitric oxide in liver injury. Curr Mol Med 3:519–526CrossRefPubMed Chen T, Zamora R, Zuckerbraun B et al (2003) Role of nitric oxide in liver injury. Curr Mol Med 3:519–526CrossRefPubMed
17.
go back to reference Vodovotz Y, Kim PK, Bagci EZ et al (2004) Inflammatory modulation of hepatocyte apoptosis by nitric oxide: in vivo, in vitro, and in silico studies. Curr Mol Med 4:753–762CrossRefPubMed Vodovotz Y, Kim PK, Bagci EZ et al (2004) Inflammatory modulation of hepatocyte apoptosis by nitric oxide: in vivo, in vitro, and in silico studies. Curr Mol Med 4:753–762CrossRefPubMed
18.
go back to reference Vallabhapurapu S, Karin M (2009) Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol 27:693–733CrossRefPubMed Vallabhapurapu S, Karin M (2009) Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol 27:693–733CrossRefPubMed
19.
go back to reference Wong ET, Tergaonkar V (2009) Roles of NF-κB in heASTh and disease: mechanisms and therapeutic potential. Clin Sci 116:451–465CrossRefPubMed Wong ET, Tergaonkar V (2009) Roles of NF-κB in heASTh and disease: mechanisms and therapeutic potential. Clin Sci 116:451–465CrossRefPubMed
20.
go back to reference Yamamoto Y, Gaynor RB (2004) IκB kinases: key regulators of the NF-κB pathway. Trends Biochem Sci 29:72–79CrossRefPubMed Yamamoto Y, Gaynor RB (2004) IκB kinases: key regulators of the NF-κB pathway. Trends Biochem Sci 29:72–79CrossRefPubMed
21.
go back to reference Wang T, Wang Y, Wu MC et al (2004) Activating mechanism of transcriptor NF-κB regulated by hepatitis B virus X protein in hepatocellular carcinoma. World J Gastroenterol 10:356–360PubMed Wang T, Wang Y, Wu MC et al (2004) Activating mechanism of transcriptor NF-κB regulated by hepatitis B virus X protein in hepatocellular carcinoma. World J Gastroenterol 10:356–360PubMed
22.
go back to reference Santoro MG, Rossi A, Amici C (2003) NF-κB and virus infection: who controls whom? EMBO J 22:2552–2560CrossRefPubMed Santoro MG, Rossi A, Amici C (2003) NF-κB and virus infection: who controls whom? EMBO J 22:2552–2560CrossRefPubMed
23.
go back to reference Feng J, Li M, Cai T et al (2005) Rotavirus-induced murine biliary atresia is mediated by nuclear factor-κB. J Pediatr Surg 40:630–636CrossRefPubMed Feng J, Li M, Cai T et al (2005) Rotavirus-induced murine biliary atresia is mediated by nuclear factor-κB. J Pediatr Surg 40:630–636CrossRefPubMed
24.
go back to reference Griscavage BS, Wilk S, Ignarro LJ et al (1996) Inhibitors of the proteasome pathway interfere with induction of nitric oxide synthase in macrophages by blocking activation of transcription factor NF-κ B. Proc Natl Acad Sci USA 93:3308–3312CrossRefPubMed Griscavage BS, Wilk S, Ignarro LJ et al (1996) Inhibitors of the proteasome pathway interfere with induction of nitric oxide synthase in macrophages by blocking activation of transcription factor NF-κ B. Proc Natl Acad Sci USA 93:3308–3312CrossRefPubMed
25.
go back to reference Taylor BS, Vera ME, Ganster RW et al (1998) Multiple NF-κ B enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J Biol Chem 273:15148–15156CrossRefPubMed Taylor BS, Vera ME, Ganster RW et al (1998) Multiple NF-κ B enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J Biol Chem 273:15148–15156CrossRefPubMed
26.
go back to reference Kleinert H, Pautz A, Linker K et al (2004) Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 500:255–266CrossRefPubMed Kleinert H, Pautz A, Linker K et al (2004) Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 500:255–266CrossRefPubMed
27.
go back to reference Vejchapipat P, Poomsawat S, Imvised T et al (2008) Overexpression of hepatic inducible nitric oxide synthase in biliary atresia. Hepatol Res 38:1018–1025CrossRefPubMed Vejchapipat P, Poomsawat S, Imvised T et al (2008) Overexpression of hepatic inducible nitric oxide synthase in biliary atresia. Hepatol Res 38:1018–1025CrossRefPubMed
28.
go back to reference Sumida W, Kaneko K, Ono Y et al (2009) Different polyunsaturated fatty acid profiles in patients with biliary atresia after successful Kasai operation and liver transplantation. Pediatr Surg Int 25:255–259CrossRefPubMed Sumida W, Kaneko K, Ono Y et al (2009) Different polyunsaturated fatty acid profiles in patients with biliary atresia after successful Kasai operation and liver transplantation. Pediatr Surg Int 25:255–259CrossRefPubMed
Metadata
Title
NF-κB related abnormal hyper-expression of iNOS and NO correlates with the inflammation procedure in biliary atresia livers
Authors
Lei Huang
Xin-Min Si
Jie-Xiong Feng
Publication date
01-09-2010
Publisher
Springer-Verlag
Published in
Pediatric Surgery International / Issue 9/2010
Print ISSN: 0179-0358
Electronic ISSN: 1437-9813
DOI
https://doi.org/10.1007/s00383-010-2683-5

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