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Published in: BMC Gastroenterology 1/2017

Open Access 01-12-2017 | Research article

Protective effects of heme oxygenase-1 against severe acute pancreatitis via inhibition of tumor necrosis factor-α and augmentation of interleukin-10

Authors: Fei-hu Zhang, Yu-han Sun, Kai-liang Fan, Xiao-bin Dong, Ning Han, Hao Zhao, Li Kong

Published in: BMC Gastroenterology | Issue 1/2017

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Abstract

Background

Heme oxygenase-1 (HO-1) is an inducible defense gene which plays a significant role in inflammation. HO-1 protects cells and tissues through the mechanism of anti-oxidation, maintaining microcirculation and anti-inflammation. The aim of the current study is to investigate the role of HO-1 on systemic inflammatory response in severe acute pancreatitis (SAP).

Methods

Forty male Sprague-Dawley (SD) rats were randomly assigned into four groups: control group (n = 10); SAP group (n = 10), SAP model was induced by retrograde injection of 3% sodium taurocholate through pancreatic duct; HO-1 stimulation group (n = 10), SD rats were injected 75 μg/kg hemin intraperitoneally 30 min after induction of SAP; HO-1 inhibition group (n = 10), SD rats were injected 20 μg/kg Zinc porphyrin (Zn-PP) intraperitoneally 30 min after induction of SAP. After 24 h of SAP establishment, tissues were collected for HO-1, tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) mRNA expression, and blood samples were collected for cytokines and biochemical measurements. Meanwhile, the histopathological changes of pancreas and liver tissues were observed.

Results

The expression of HO-1 mRNA and protein were significantly induced by SAP in rat pancreas and liver. Hemin treatment significantly decreased oxidative stress and TNF-α in plasma and tissues, while the IL-10 was significantly increased. Pancreas and liver injury induced by SAP was markedly attenuated by Hemin treatment. Moreover, inhibition of HO-1 expression by Zn-PP administration aggravated the injury caused by SAP.

Conclusions

Induction of HO-1 in early SAP may modulate systemic inflammatory response and prevent pancreas and nearby organs such as liver injury through inhibition of TNF-α and augmentation of IL-10.
Literature
2.
go back to reference Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guideline for the management of acute pancreatitis. Pancreatology. 2013;13:e1–15.CrossRef Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guideline for the management of acute pancreatitis. Pancreatology. 2013;13:e1–15.CrossRef
3.
go back to reference Zhang F, Fei J, Zhao B, Chen E, Mao E. Protective effect of adenoviral transfer of heme oxygenase-1 gene on rats with severe acute pancreatitis. Am J Med Sci. 2014;348(3):224–31.CrossRefPubMed Zhang F, Fei J, Zhao B, Chen E, Mao E. Protective effect of adenoviral transfer of heme oxygenase-1 gene on rats with severe acute pancreatitis. Am J Med Sci. 2014;348(3):224–31.CrossRefPubMed
4.
go back to reference Anand N, Park JH, Wu BU. Modern management of acute pancreatitis. Gastroenterol Clin N Am. 2012;41(1):1–8.CrossRef Anand N, Park JH, Wu BU. Modern management of acute pancreatitis. Gastroenterol Clin N Am. 2012;41(1):1–8.CrossRef
5.
go back to reference Moretti AI, Rios EC, Soriano FG, de Souza HP, Abatepaulo F, Barbeiro DF, Velasco IT. Acute pancreatitis hypertonic saline increases heat shock proteins 70 and 90 and reduces neotrophil infiltration in lung injury. Pancreas. 2009;38(5):507–14.CrossRefPubMed Moretti AI, Rios EC, Soriano FG, de Souza HP, Abatepaulo F, Barbeiro DF, Velasco IT. Acute pancreatitis hypertonic saline increases heat shock proteins 70 and 90 and reduces neotrophil infiltration in lung injury. Pancreas. 2009;38(5):507–14.CrossRefPubMed
6.
go back to reference Saluja A, Deduja V. Heat shock proteins in pancreatic diseaes. J Gastroenterol Hepatol. 2008;23:S42–5.CrossRefPubMed Saluja A, Deduja V. Heat shock proteins in pancreatic diseaes. J Gastroenterol Hepatol. 2008;23:S42–5.CrossRefPubMed
7.
go back to reference Nakamichil I, Habtezion A, Zhong B, Contag CH, Butcher EC, Omary MB. Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest. 2005;115:3007–14.CrossRef Nakamichil I, Habtezion A, Zhong B, Contag CH, Butcher EC, Omary MB. Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest. 2005;115:3007–14.CrossRef
8.
go back to reference Abraham NG, Asija A, Drummond G, Peterson S. Heme oxygenase-1 gene therapy : recent advances and therapeutic applications. Curr Gene Ther. 2007;7(2):89–108.CrossRefPubMed Abraham NG, Asija A, Drummond G, Peterson S. Heme oxygenase-1 gene therapy : recent advances and therapeutic applications. Curr Gene Ther. 2007;7(2):89–108.CrossRefPubMed
9.
go back to reference Tamion F, Richard V, Renet S, Thuillez C. Protective effects of heme-oxgenase expression against endotoxic shock: inhibition of tumor necrosis factor-alpha and augmentation of interleukin-10. J Trauma. 2006;61(5):1078–84.CrossRefPubMed Tamion F, Richard V, Renet S, Thuillez C. Protective effects of heme-oxgenase expression against endotoxic shock: inhibition of tumor necrosis factor-alpha and augmentation of interleukin-10. J Trauma. 2006;61(5):1078–84.CrossRefPubMed
10.
go back to reference Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nature Med. 2002;8:240–6.CrossRefPubMed Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nature Med. 2002;8:240–6.CrossRefPubMed
11.
go back to reference Gulla A, Evans BJ, Navenot JM, Pundzius J, Barauskas G, Gulbinas A, Dambrauskas Z, Arafat H, Wang ZX. Heme oxygenase-1 gene promoter polymorphism is associateed with the development of necrotizing acute pancreatitis. Pancreas. 2014;43(8):1271–6.CrossRefPubMed Gulla A, Evans BJ, Navenot JM, Pundzius J, Barauskas G, Gulbinas A, Dambrauskas Z, Arafat H, Wang ZX. Heme oxygenase-1 gene promoter polymorphism is associateed with the development of necrotizing acute pancreatitis. Pancreas. 2014;43(8):1271–6.CrossRefPubMed
12.
go back to reference Pellacani A, Wiesel P, Sharma A, Foster LC, Huggins GS, Yet SF, Perrella MA. Induction of heme oxygenase-1 during endotoxemia is downregulated by transforming growth factor-betal. Circ Res. 1998;83(4):396–403.CrossRefPubMed Pellacani A, Wiesel P, Sharma A, Foster LC, Huggins GS, Yet SF, Perrella MA. Induction of heme oxygenase-1 during endotoxemia is downregulated by transforming growth factor-betal. Circ Res. 1998;83(4):396–403.CrossRefPubMed
13.
go back to reference Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefel WT, Warshaw AL. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992;215:44–56.CrossRefPubMedPubMedCentral Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefel WT, Warshaw AL. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992;215:44–56.CrossRefPubMedPubMedCentral
14.
go back to reference Sass G, Barikbin R, Tiegs G. The multiple functions of heme oxygenase-1 in the liver. Z Gastroenterol. 2012;50(1):34–40.CrossRefPubMed Sass G, Barikbin R, Tiegs G. The multiple functions of heme oxygenase-1 in the liver. Z Gastroenterol. 2012;50(1):34–40.CrossRefPubMed
15.
go back to reference Zhu X, Fan WG, Li DP, Kung H, Lin MC. Heme oxygenase-1 system and gastronintestinal inflammation: a short review. World J Gastroenterol. 2011;17(38):4283–8.CrossRefPubMedPubMedCentral Zhu X, Fan WG, Li DP, Kung H, Lin MC. Heme oxygenase-1 system and gastronintestinal inflammation: a short review. World J Gastroenterol. 2011;17(38):4283–8.CrossRefPubMedPubMedCentral
16.
go back to reference Saruc M, Yuceyar H, Turkel N, Ozutemiz O, Tuzcuoglu I, Ayhan S, Yuce G, Coker I, Huseyino A. The role of heme in hemolysis-induced acute pancreatitis. Med Sci Monit. 2007;13(3):BR67–72.PubMed Saruc M, Yuceyar H, Turkel N, Ozutemiz O, Tuzcuoglu I, Ayhan S, Yuce G, Coker I, Huseyino A. The role of heme in hemolysis-induced acute pancreatitis. Med Sci Monit. 2007;13(3):BR67–72.PubMed
17.
go back to reference Castilho A, Aveleira CA, Leal EC, Simoes NF, Fernandes CR, Meirinhos RI, Baptista FI, Ambrosio AF. Heme oxygenase-1 protects retinal endothelial cells against high glucose- and oxidative/nitrosative stress-induced toxicity. PLoS One. 2012;7(8):e42428.CrossRefPubMedPubMedCentral Castilho A, Aveleira CA, Leal EC, Simoes NF, Fernandes CR, Meirinhos RI, Baptista FI, Ambrosio AF. Heme oxygenase-1 protects retinal endothelial cells against high glucose- and oxidative/nitrosative stress-induced toxicity. PLoS One. 2012;7(8):e42428.CrossRefPubMedPubMedCentral
18.
go back to reference Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S. Role of tumor necrosis factor-alpha in avute pancreatitis: from biological basia to clinical evidence. Shock. 2007;28(2):130–40.CrossRefPubMed Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S. Role of tumor necrosis factor-alpha in avute pancreatitis: from biological basia to clinical evidence. Shock. 2007;28(2):130–40.CrossRefPubMed
19.
go back to reference Bishehsari F, Sharma A, Stello K, Toth C, O’Connell MR, Evans AC, LaRusch J, Muddana V, Papachristou GI, Whitcomb DC. TNF-alpha gene (TNFA) variants increase risk for muti-origan dysfunction syndrome (MODS) in acute pancreatitis. Pancreatology. 2012;12(2):113–8.CrossRefPubMedPubMedCentral Bishehsari F, Sharma A, Stello K, Toth C, O’Connell MR, Evans AC, LaRusch J, Muddana V, Papachristou GI, Whitcomb DC. TNF-alpha gene (TNFA) variants increase risk for muti-origan dysfunction syndrome (MODS) in acute pancreatitis. Pancreatology. 2012;12(2):113–8.CrossRefPubMedPubMedCentral
20.
go back to reference Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology. 1997;112(3):960–7.CrossRefPubMed Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology. 1997;112(3):960–7.CrossRefPubMed
21.
go back to reference Grewal HP, Mohey el Din A, Gaber L, Kotb M, Gaber AO. Ameliroration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg. 1994;167(1):214–8.CrossRefPubMed Grewal HP, Mohey el Din A, Gaber L, Kotb M, Gaber AO. Ameliroration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg. 1994;167(1):214–8.CrossRefPubMed
22.
go back to reference De Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin 10. Ann Med. 1995;27(5):537–41.CrossRefPubMed De Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin 10. Ann Med. 1995;27(5):537–41.CrossRefPubMed
23.
go back to reference Chen ZQ, Tang YQ, Zhang Y, Jiang ZH, Mao EQ, Zou WG, Lei RQ, Han TQ, Zhang SD. Adenoviral transfer of human interleukin-10 gene in lethal pancreatitis. World J Gastroenterol. 2004;10(20):3021–5.CrossRefPubMedPubMedCentral Chen ZQ, Tang YQ, Zhang Y, Jiang ZH, Mao EQ, Zou WG, Lei RQ, Han TQ, Zhang SD. Adenoviral transfer of human interleukin-10 gene in lethal pancreatitis. World J Gastroenterol. 2004;10(20):3021–5.CrossRefPubMedPubMedCentral
24.
go back to reference Morse D, Choi AM. Heme-oxygenase-1: the “emerging molecule” has arrived. Am J Respir Cell Mol Biol. 2002;283:L476–84. Morse D, Choi AM. Heme-oxygenase-1: the “emerging molecule” has arrived. Am J Respir Cell Mol Biol. 2002;283:L476–84.
25.
go back to reference Tosaki A, Das DK. The role of heme oxygenase signaling in various disorders. Mol Cell Biochem. 2002;232:149–57.CrossRefPubMed Tosaki A, Das DK. The role of heme oxygenase signaling in various disorders. Mol Cell Biochem. 2002;232:149–57.CrossRefPubMed
26.
go back to reference Petrache I, Otterbein LE, Alam J, Wiegand GW, Choi AM. Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2000;278:L312–9.PubMed Petrache I, Otterbein LE, Alam J, Wiegand GW, Choi AM. Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2000;278:L312–9.PubMed
27.
go back to reference Ryter SW, Tyrrell RM. The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med. 2000;28:289–309.CrossRefPubMed Ryter SW, Tyrrell RM. The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med. 2000;28:289–309.CrossRefPubMed
28.
go back to reference Morse D, Choi AM. Heme oxygenase-1: from bench to bedside. Am J Respir Crit Care Med. 2005;172(6):660–70.CrossRefPubMed Morse D, Choi AM. Heme oxygenase-1: from bench to bedside. Am J Respir Crit Care Med. 2005;172(6):660–70.CrossRefPubMed
29.
go back to reference Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6:4222–428. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6:4222–428.
30.
go back to reference Morse D, Pischke SE, Zhou Z, Davis RJ, Flavell RA, Loop T, Otterbein SL, Otterbein LE, Choi AM. Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J Biol Chem. 2003;278:36993–8.CrossRefPubMed Morse D, Pischke SE, Zhou Z, Davis RJ, Flavell RA, Loop T, Otterbein SL, Otterbein LE, Choi AM. Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J Biol Chem. 2003;278:36993–8.CrossRefPubMed
31.
32.
go back to reference Liu B, Qian JM. Cytoprotective role of heme oxygenase-1 in liver ischemia reperfusion injury. Int J Clin Exp Med. 2015;8(11):19867–73.PubMedPubMedCentral Liu B, Qian JM. Cytoprotective role of heme oxygenase-1 in liver ischemia reperfusion injury. Int J Clin Exp Med. 2015;8(11):19867–73.PubMedPubMedCentral
33.
go back to reference Scharn CR, Collins AC, Nair VR, Stamm CE, Marciano DK, Graviss EA, Shiloh MU. Heme oxygenase-1 regulates inflammation and mycobacterial survival in human macrophages during mycobacterium tuberculosis infection. J Immunol. 2016;196(11):4641–9.CrossRefPubMedPubMedCentral Scharn CR, Collins AC, Nair VR, Stamm CE, Marciano DK, Graviss EA, Shiloh MU. Heme oxygenase-1 regulates inflammation and mycobacterial survival in human macrophages during mycobacterium tuberculosis infection. J Immunol. 2016;196(11):4641–9.CrossRefPubMedPubMedCentral
34.
go back to reference Ciesla M, Marona P, Kozakowska M, Jez M, Seczynska M, Loboda A, Bukowska-Strakova K, Szade A, Walawender M, Kusior M, et al. Heme oxygenase-1 controls an HDAC4-miR-206 pathway of oxidative stress in rhabdomyosarcoma. Cancer Res. 2016;76(19):5707–18.CrossRefPubMed Ciesla M, Marona P, Kozakowska M, Jez M, Seczynska M, Loboda A, Bukowska-Strakova K, Szade A, Walawender M, Kusior M, et al. Heme oxygenase-1 controls an HDAC4-miR-206 pathway of oxidative stress in rhabdomyosarcoma. Cancer Res. 2016;76(19):5707–18.CrossRefPubMed
35.
go back to reference Wang L, Zhao B, Chen Y, Ma L, Chen EZ, Mao EQ. Biliary tract external drainage increases the expression levels of heme oxygenase-1 in rat livers. Eur J Med Res. 2015;22(20):61.CrossRef Wang L, Zhao B, Chen Y, Ma L, Chen EZ, Mao EQ. Biliary tract external drainage increases the expression levels of heme oxygenase-1 in rat livers. Eur J Med Res. 2015;22(20):61.CrossRef
36.
go back to reference Weis S, Jesinghaus M, Kovacs P, Schleinitz D, Schober R, Ruffert C, Herms M, Wittenburg H, Stumvoll M, Bluher M, et al. Genetic analyses of heme oxygenase 1 (HMOX1) in different forms of pancreatitis. PLoS One. 2012;7(5):e37981.CrossRefPubMedPubMedCentral Weis S, Jesinghaus M, Kovacs P, Schleinitz D, Schober R, Ruffert C, Herms M, Wittenburg H, Stumvoll M, Bluher M, et al. Genetic analyses of heme oxygenase 1 (HMOX1) in different forms of pancreatitis. PLoS One. 2012;7(5):e37981.CrossRefPubMedPubMedCentral
37.
go back to reference Habtezion A, Kwan R, Yang AL, Morgan ME, Akhtar E, Wanaski SP, Collins SD, Butcher EC, Kamal A, Omary MB. Heme oxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: a potential therapeutic target. Am J Physiol Gastrointest Liver Physiol. 2011;300(1):G12–20.CrossRefPubMed Habtezion A, Kwan R, Yang AL, Morgan ME, Akhtar E, Wanaski SP, Collins SD, Butcher EC, Kamal A, Omary MB. Heme oxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: a potential therapeutic target. Am J Physiol Gastrointest Liver Physiol. 2011;300(1):G12–20.CrossRefPubMed
38.
go back to reference Singh U, Devaraj S, Jialal I. Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr. 2005;25:151–74.CrossRefPubMed Singh U, Devaraj S, Jialal I. Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr. 2005;25:151–74.CrossRefPubMed
39.
go back to reference Lorente JA, Marshall JC. Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock. 2005;1:107–19.CrossRef Lorente JA, Marshall JC. Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock. 2005;1:107–19.CrossRef
40.
go back to reference Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S. TNF-alpha as a therapeutic target in acute pancreatitis-lessons from experimental models. Sci World J. 2007;7:431–48.CrossRef Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S. TNF-alpha as a therapeutic target in acute pancreatitis-lessons from experimental models. Sci World J. 2007;7:431–48.CrossRef
Metadata
Title
Protective effects of heme oxygenase-1 against severe acute pancreatitis via inhibition of tumor necrosis factor-α and augmentation of interleukin-10
Authors
Fei-hu Zhang
Yu-han Sun
Kai-liang Fan
Xiao-bin Dong
Ning Han
Hao Zhao
Li Kong
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2017
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/s12876-017-0651-4

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