Heme oxygenase/carbon monoxide pathway inhibition plays a role in ameliorating fibrosis following splenectomy

Wang,Qiu-Ming; Duan,Zhi-Jun; Du,Jian-Ling; Guo,Shi-Bin; Sun,Xiao-Yu; Liu,Zhen

doi:10.3892/ijmm.2013.1309

Heme oxygenase/carbon monoxide pathway inhibition plays a role in ameliorating fibrosis following splenectomy

Authors:
- Qiu-Ming Wang
- Zhi-Jun Duan
- Jian-Ling Du
- Shi-Bin Guo
- Xiao-Yu Sun
- Zhen Liu
View Affiliations

Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: March 20, 2013 https://doi.org/10.3892/ijmm.2013.1309
Pages: 1186-1194

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Splenectomy is a recognized therapy for liver cirrhosis with splenomegaly, since it decreases free iron concentration that accompanies the destruction of red blood cells. Heme oxygenase (HO)-1 and its by-products, iron and carbon monoxide (CO), play crucial roles in hepatic fibrosis. The aim of the present study was to determine whether splenectomy in cirrhotic rats induced by bile duct ligation (BDL), through the HO/CO pathway, could slow down the development of liver fibrosis. Male Sprague-Dawley rats were divided randomly into the sham, BDL, splenectomy, Fe, zinc protoporphyrin (Znpp) and cobalt protoporphyrin (Copp) treatment groups, for inhibiting and inducing HO-1 expression. The level of HO-1 was detected by western blot analysis and reverse transcription-polymerase chain reaction. Serum carboxyhemoglobin (COHb), iron and portal vein pressure (PVP) were also quantified. Liver iron was measured by atomic absorption spectrometry with acetylene-air flame atomization. HO-1 and α-smooth muscle actin (α-SMA) were localized by immunohistochemistry. Liver and spleen iron were visualized by Perls' Prussian blue staining. Hepatic fibrosis was assessed using hematoxylin and eosin (H&E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum transforming growth factor-β1 (TGF-β1). The results showed that liver, spleen and serum levels of HO-1, COHb and iron were greatly enhanced in the BDL group compared with the sham group; they were reduced following splenectomy and Znpp treatment, but were elevated in the Copp and Fe groups. Hydroxyproline, TGF-β1, α-SMA, PVP and malonaldehyde levels were lower in the splenectomy and Znpp groups compared to BDL, while higher levels were observed in the Copp and Fe-treated groups. Our study shows that splenectomy reduces iron and CO levels in part by reducing HO-1 expression, and it decreases portal pressure and slightly decreases hepatic fibroproliferation.

View Figures

View References

1	Imura S, Shimada M, Utsunomiya T, et al: Impact of splenectomy in patients with liver cirrhosis: Results from 18 patients in a single center experience. Hepatol Res. 40:894–900. 2010. View Article : Google Scholar : PubMed/NCBI
2	Ito K, Ozasa H, Noda Y and Horikawa S: Splenic artery ligation ameliorates hepatic ischemia and reperfusion injury in rats. Liver Int. 26:254–260. 2006. View Article : Google Scholar : PubMed/NCBI
3	Ito K, Ozasa H and Horikawa S: Effects of prior splenectomy on remnant liver after partial hepatectomy with Pringle maneuver in rats. Liver Int. 25:438–444. 2005. View Article : Google Scholar : PubMed/NCBI
4	Shimada M, Ijichi H, Yonemura Y, et al: The impact of splenectomy or splenic artery ligation on the outcome of a living donor adult liver transplantation using a left lobe graft. Hepatogastroenterology. 51:625–629. 2004.PubMed/NCBI
5	Chen XP, Wu ZD, Huang ZY and Qiu FZ: Use of hepatectomy and splenectomy to treat hepatocellular carcinoma with cirrhotic hypersplenism. Br J Surg. 92:334–339. 2005. View Article : Google Scholar : PubMed/NCBI
6	Uehara H, Akahoshi T, Kawanaka H, et al: Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis. Hepatol Res. 42:1039–1047. 2012. View Article : Google Scholar : PubMed/NCBI
7	Arakawa Y, Shimada M, Uchiyama H, et al: Beneficial effects of splenectomy on massive hepatectomy model in rats. Hepatol Res. 39:391–397. 2009. View Article : Google Scholar : PubMed/NCBI
8	Ito K, Ozasa H, Yoneya R and Horikawa S: Splenectomy ameliorates hepatic ischemia and reperfusion injury mediated by heme oxygenase-1 induction in the rat. Liver. 22:467–473. 2002. View Article : Google Scholar : PubMed/NCBI
9	Tarquini R, Masini E, La Villa G, et al: Increased plasma carbon monoxide in patients with viral cirrhosis and hyperdynamic circulation. Am J Gastroenterol. 104:891–897. 2009. View Article : Google Scholar : PubMed/NCBI
10	Duan ZJ, Yang D, Wang F, Sun YJ, Sun XY and Zheng ML: Heme oxygenase-1 regulates the major route involved in formation of immune hepatic fibrosis in rats. Chin Med J. 123:3304–3308. 2010.PubMed/NCBI
11	Sass G, Barikbin R and Tiegs G: The multiple functions of heme oxygenase-1 in the liver. Z Gastroenterol. 50:34–40. 2012. View Article : Google Scholar : PubMed/NCBI
12	Naik JS, O’Donaughy TL and Walker BR: Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation. Am J Physiol Heart Circ Physiol. 284:H838–H845. 2003. View Article : Google Scholar : PubMed/NCBI
13	Guo SB, Duan ZJ, Li Q and Sun XY: Effect of heme oxygenase-1 on renal function in rats with liver cirrhosis. World J Gastroenterol. 17:322–328. 2011. View Article : Google Scholar : PubMed/NCBI
14	Guo SB, Duan ZJ, Li Q and Sun XY: Effects of heme oxygenase-1 on pulmonary function and structure in rats with liver cirrhosis. Chin Med J. 124:918–922. 2011.PubMed/NCBI
15	Iwamoto T, Terai S, Mizunaga Y, et al: Splenectomy enhances the anti-fibrotic effect of bone marrow cell infusion and improves liver function in cirrhotic mice and patients. J Gastroenterol. 47:300–312. 2012. View Article : Google Scholar : PubMed/NCBI
16	Brown KE, Dennery PA, Ridnour LA, et al: Effect of iron overload and dietary fat on indices of oxidative stress and hepatic fibrogenesis in rats. Liver Int. 23:232–242. 2003. View Article : Google Scholar : PubMed/NCBI
17	Fallon MB, Abrams GA, McGrath JW, Hou Z and Luo B: Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome. Am J Physiol. 272:G779–G784. 1997.PubMed/NCBI
18	Luo B, Abrams GA and Fallon MB: Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction. J Hepatol. 29:571–578. 1998. View Article : Google Scholar : PubMed/NCBI
19	Shackelford C, Long G, Wolf J, Okerberg C and Herbert R: Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies. Toxicol Pathol. 30:93–96. 2002. View Article : Google Scholar : PubMed/NCBI
20	Kakinuma S, Tanaka Y, Chinzei R, et al: Human umbilical cord blood as a source of transplantable hepatic progenitor cells. Stem Cells. 21:217–227. 2003.PubMed/NCBI
21	Ueda S, Yamanoi A, Hishikawa Y, Dhar DK, Tachibana M and Nagasue N: Transforming growth factor-beta1 released from the spleen exerts a growth inhibitory effect on liver regeneration in rats. Lab Invest. 83:1595–1603. 2003. View Article : Google Scholar : PubMed/NCBI
22	Akahoshi T, Hashizume M, Tanoue K, et al: Role of the spleen in liver fibrosis in rats may be mediated by transforming growth factor beta-1. J Gastroenterol Hepatol. 17:59–65. 2002. View Article : Google Scholar : PubMed/NCBI
23	Giles TD, Sander GE, Nossaman BD and Kadowitz PJ: Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens. 14:198–205. 2012. View Article : Google Scholar
24	Johnson RA, Kozma F and Colombari E: Carbon monoxide: from toxin to endogenous modulator of cardiovascular functions. Braz J Med Biol Res. 32:1–14. 1999. View Article : Google Scholar : PubMed/NCBI
25	Furchgott RF and Jothianandan D: Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 28:52–61. 1991.
26	Decaluwe K, Pauwels B, Verpoest S and Van de Voorde J: Divergent mechanisms involved in CO and CORM-2 induced vasorelaxation. Eur J Pharmacol. 674:370–377. 2012. View Article : Google Scholar : PubMed/NCBI
27	Carter EP, Hartsfield CL, Miyazono M, Jakkula M, Morris KG Jr and McMurtry IF: Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol. 283:L346–L353. 2002. View Article : Google Scholar : PubMed/NCBI
28	Wang F, Duan ZJ and Sun YJ: Influence of heme oxygenase-1 expression on immune liver fibrosis induced by cobalt protoporphyrin in rats. World J Gastroenterol. 15:3009–3014. 2009. View Article : Google Scholar : PubMed/NCBI
29	Barikbin R, Neureiter D, Wirth J, et al: Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice. Hepatology. 55:553–562. 2012. View Article : Google Scholar : PubMed/NCBI
30	Khan ZA, Barbin YP, Cukiernik M, Adams PC and Chakrabarti S: Heme-oxygenase-mediated iron accumulation in the liver. Can J Physiol Pharmacol. 82:448–456. 2004. View Article : Google Scholar : PubMed/NCBI
31	Kartikasari AE, Wagener FA, Yachie A, Wiegerinck ET, Kemna EH and Swinkels DW: Hepcidin suppression and defective iron recycling account for dysregulation of iron homeostasis in heme oxygenase-1 deficiency. J Cell Mol Med. 13:3091–3102. 2009. View Article : Google Scholar : PubMed/NCBI
32	Crichton RR, Wilmet S, Legssyer R and Ward RJ: Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem. 91:9–18. 2002. View Article : Google Scholar : PubMed/NCBI
33	Immenschuh S, Baumgart-Vogt E and Mueller S: Heme oxygenase-1 and iron in liver inflammation: a complex alliance. Curr Drug Targets. 11:1541–1550. 2010. View Article : Google Scholar : PubMed/NCBI
34	Ramm GA and Ruddell RG: Iron homeostasis, hepatocellular injury, and fibrogenesis in hemochromatosis: the role of inflammation in a noninflammatory liver disease. Semin Liver Dis. 30:271–287. 2010. View Article : Google Scholar : PubMed/NCBI
35	Pietrangelo A: Metals, oxidative stress, and hepatic fibrogenesis. Semin Liver Dis. 16:13–30. 1996. View Article : Google Scholar
36	Deugnier Y and Turlin B: Pathology of hepatic iron overload. Semin Liver Dis. 31:260–271. 2011. View Article : Google Scholar
37	Chen YC, Gines P, Yang J, et al: Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats. Hepatology. 39:1075–1087. 2004. View Article : Google Scholar : PubMed/NCBI
38	Shi BM, Wang XY, Mu QL, Wu TH and Xu J: Value of portal hemodynamics and hypersplenism in cirrhosis staging. World J Gastroenterol. 11:708–711. 2005. View Article : Google Scholar : PubMed/NCBI
39	Valero MA, Girones N, Garcia-Bodelon MA, et al: Anaemia in advanced chronic fasciolosis. Acta Trop. 108:35–43. 2008. View Article : Google Scholar : PubMed/NCBI
40	Rhyu DY, Park J, Sharma BR and Ha H: Role of reactive oxygen species in transforming growth factor-beta1-induced extracellular matrix accumulation in renal tubular epithelial cells. Transplant Proc. 44:625–628. 2012. View Article : Google Scholar
41	Urtasun R, Conde de la Rosa L and Nieto N: Oxidative and nitrosative stress and fibrogenic response. Clin Liver Dis. 12:769–790. viii2008. View Article : Google Scholar : PubMed/NCBI
42	Yao P, Nussler A, Liu L, et al: Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol. 47:253–261. 2007. View Article : Google Scholar : PubMed/NCBI
43	Okada K, Warabi E, Sugimoto H, et al: Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis. J Gastroenterol. 47:924–935. 2012. View Article : Google Scholar : PubMed/NCBI