Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Guo,Shi-Bin; Li,Qing; Duan,Zhi-Jun; Wang,Qiu-Ming; Zhou,Qin; Sun,Xiao-Yu

doi:10.3892/mmr.2014.2735

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Authors:
- Shi-Bin Guo
- Qing Li
- Zhi-Jun Duan
- Qiu-Ming Wang
- Qin Zhou
- Xiao-Yu Sun
View Affiliations

Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 0086-116011, P.R. China, Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 0086-116011, P.R. China
Published online on: October 22, 2014 https://doi.org/10.3892/mmr.2014.2735
Pages: 83-90
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase‑1 (HO‑1) expression, together with the influence of altered hepatic HO‑1 expression levels on hepatic function and fibrosis in bile duct‑ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO‑1 mRNA were measured by reverse‑transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson's staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO‑1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide‑treated group exhibited significantly reduced hepatic HO‑1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO‑1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO‑1 overexpression in cirrhotic rats, reduced hepatic HO‑1 expression levels to relieve liver injury and attenuated liver fibrosis.

View Figures

View References

1	Montaño-Loza A and Meza-Junco J: Pathogenesis of portal hypertension. Rev Invest Clin. 57:596–607. 2005.(In Spanish).
2	Augustin S, González A and Genescà J: Acute esophageal variceal bleeding: Current strategies and new perspectives. World J Hepatol. 2:261–274. 2010. View Article : Google Scholar : PubMed/NCBI
3	Bosch J and Abraldes JG: Variceal bleeding: pharmacological therapy. Dig Dis. 23:18–29. 2005. View Article : Google Scholar : PubMed/NCBI
4	Reyes Dorantes AA: Endoscopic management of variceal bleeding. Rev Gastroenterol Mex. 70:50–55. 2005.(In Spanish).
5	Zhou DX, Zhou HB, Wang Q, et al: The effectiveness of the treatment of octreotide on chylous ascites after liver cirrhosis. Dig Dis Sci. 54:1783–1788. 2009. View Article : Google Scholar : PubMed/NCBI
6	Kim YM, Pae HO, Park JE, et al: Heme oxygenase in the regulation of vascular biology: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 14:137–167. 2011. View Article : Google Scholar : PubMed/NCBI
7	Ryter SW and Choi AM: Heme oxygenase-1/carbon monoxide: from metabolism to molecular therapy. Am J Respir Cell Mol Biol. 41:251–260. 2009. View Article : Google Scholar : PubMed/NCBI
8	Kwok SC: Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway. Int J Cell Biol. 2013:1620942013.PubMed/NCBI
9	Leffler CW, Parfenova H, Jaggar JH and Wang R: Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation. J App Physiol. 100:1065–1076. 2006. View Article : Google Scholar : PubMed/NCBI
10	Li Volti G, Sacerdoti D, Di Giacomo C, et al: Natural heme oxygenase-1 inducers in hepatobiliary function. World J Gastroenterol. 14:6122–6132. 2008.PubMed/NCBI
11	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
12	Pereira RM, dos Santos RA, Oliveira EA, et al: Development of hepatorenal syndrome in bile duct ligated rats. World J Gastroenterology. 14:4505–4511. 2008. View Article : Google Scholar : PubMed/NCBI
13	Amersi F, Buelow R, Kato H, et al: Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest. 104:1631–1639. 1999. View Article : Google Scholar : PubMed/NCBI
14	Tilney HS, Lovegrove RE, Purkayastha S, et al: Comparison of colonic stenting and open surgery for malignant large bowel obstruction. Surg Endosc. 21:225–233. 2007. View Article : Google Scholar : PubMed/NCBI
15	Brown KE, Poulos JE, Li L, et al: Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload. Am J Physiol. 272:G116–G123. 1997.PubMed/NCBI
16	Prentø P: Van Gieson’s picrofuchsin. The staining mechanisms for collagen and cytoplasm, and an examination of the dye diffusion rate model of differential staining. Histochemistry. 99:163–174. 1993.
17	Kakinuma S1, 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
18	Makino N, Suematsu M, Sugiura Y, et al: Altered expression of heme oxygenase-1 in the livers of patients with portal hypertensive diseases. Hepatology. 33:32–42. 2001. View Article : Google Scholar : PubMed/NCBI
19	Wei CL, Lee KH, Khoo HE and Hon WM: Expression of haem oxygenase in cirrhotic rat liver. J Pathol. 199:324–334. 2003. View Article : Google Scholar : PubMed/NCBI
20	Thabut D and Bernard-Chabert B: Management of acute bleeding from portal hypertension. Best Pract Res Clin Gastroenterol. 21:19–29. 2007. View Article : Google Scholar : PubMed/NCBI
21	Dib N, Oberti F and Calès P: Current management of the complications of portal hypertension: variceal bleeding and ascites. CMAJ. 174:1433–1443. 2006. View Article : Google Scholar : PubMed/NCBI
22	Mileti E and Rosenthal P: Management of portal hypertension in children. Curr Gastroenterol Rep. 13:10–16. 2011. View Article : Google Scholar : PubMed/NCBI
23	Reynaert H and Geerts A: Pharmacological rationale for the use of somatostatin and analogues in portal hypertension. Aliment Pharmacol Ther. 18:375–386. 2003. View Article : Google Scholar : PubMed/NCBI
24	Gøtzsche PC and Hróbjartsson A: Somatostatin analogues for acute bleeding oesophageal varices. Cochrane Database Syst Rev. 2008:CD0001932008.
25	Zhang HB, Wong BC, Zhou XM, et al: Effects of somatostatin, octreotide and pitressin plus nitroglycerine on systemic and portal haemodynamics in the control of acute variceal bleeding. Int J Clin Pract. 56:447–451. 2002.PubMed/NCBI
26	Rodriguez F, Kemp R, Balazy M and Nasjletti A: Effects of exogenous heme on renal function: role of heme oxygenase and cyclooxygenase. Hypertension. 42:680–684. 2003. View Article : Google Scholar : PubMed/NCBI
27	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.PubMed/NCBI
28	Carter EP, Hartsfield CL, Miyazono M, et al: Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol. 283:L346–L353. 2002.PubMed/NCBI
29	Pae HO, Lee YC and Chung HT: Heme oxygenase-1 and carbon monoxide: emerging therapeutic targets in inflammation and allergy. Recent Pat Inflamm Allergy Drug Discov. 2:159–165. 2008. View Article : Google Scholar : PubMed/NCBI
30	Ashino T, Yamanaka R, Yamamoto M, et al: Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages. Mol Immunol. 45:2106–2115. 2008. View Article : Google Scholar : PubMed/NCBI
31	Naik JS and Walker BR: Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization. Am J Physiol Heart Circ Physiol. 285:H220–H228. 2003.PubMed/NCBI
32	Xi Q, Tcheranova D, Parfenova H, et al: Carbon monoxide activates KCa channels in newborn arteriole smooth muscle cells by increasing apparent Ca2+ sensitivity of alpha-subunits. Am J Physiol Heart Circ Physiol. 286:H610–H618. 2004. View Article : Google Scholar : PubMed/NCBI
33	Blendis L and Wong F: The hyperdynamic circulation in cirrhosis: an overview. Pharmacol Ther. 89:221–231. 2001. View Article : Google Scholar : PubMed/NCBI
34	Kim MY and Baik SK: Hyperdynamic circulation in patients with liver cirrhosis and portal hypertension. Korean J Gastroenterol. 54:143–148. 2009. View Article : Google Scholar : PubMed/NCBI
35	Froh M, Conzelmann L, Walbrun P, et al: Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats. World J Gastroenterol. 13:3478–3486. 2007. View Article : Google Scholar : PubMed/NCBI
36	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 (Engl). 124:918–922. 2011.PubMed/NCBI
37	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
38	Yang H, Zhao LF, Zhao ZF, et al: Heme oxygenase-1 prevents liver fibrosis in rats by regulating the expression of PPARgamma and NF-kappaB. World J Gastroenterol. 18:1680–1688. 2012. View Article : Google Scholar : PubMed/NCBI
39	Malaguarnera L, Madeddu R, Palio E, Arena N and Malaguarnera M: Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. J Hepatol. 42:585–591. 2005. View Article : Google Scholar : PubMed/NCBI
40	Wen T, Guan L, Zhang YL and Zhao JY: Dynamic changes of heme oxygenase-1 and carbon monoxide production in acute liver injury induced by carbon tetrachloride in rats. Toxicology. 228:51–57. 2006. View Article : Google Scholar : PubMed/NCBI
41	Zeng Z, Huang HF, Chen MQ, Song F and Zhang YJ: Heme oxygenase-1 protects donor livers from ischemia/reperfusion injury: the role of Kupffer cells. World J Gastroenterol. 16:1285–1292. 2010. View Article : Google Scholar : PubMed/NCBI
42	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
43	Wang QM, Duan ZJ, Du JL, et al: Heme oxygenase/carbon monoxide pathway inhibition plays a role in ameliorating fibrosis following splenectomy. Int J Mol Med. 31:1186–1194. 2013.PubMed/NCBI
44	Geuken E, Buis CI, Visser DS, et al: Expression of heme oxygenase-1 in human livers before transplantation correlates with graft injury and function after transplantation. Am J Transplant. 5:1875–1885. 2005. View Article : Google Scholar : PubMed/NCBI
45	Duan ZJ, Yang D, Wang F, et al: Heme oxygenase-1 regulates the major route involved in formation of immune hepatic fibrosis in rats. Chinese Med J (Engl). 123:3304–3308. 2010.PubMed/NCBI
46	Wang QM, Du JL, Duan ZJ, et al: Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation. World J Gastroenterol. 19:2921–2934. 2013.PubMed/NCBI
47	Wang QM, Yin XY, Duan ZJ, Guo SB and Sun XY: Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy. Mol Med Rep. 8:67–74. 2013.PubMed/NCBI