Mucosa repair mechanisms of Tong-Xie-Yao-Fang mediated by CRH-R2 in murine, dextran sulfate sodium-induced colitis
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摘要
AIM To explore the significance of corticotropin-releasing hormone(CRH)-receptor(R)2 in mucosal healing of dextran sulfate sodium(DSS)-induced colitis and the effect of Tong-Xie-Yao-Fang(TXYF) on CRH-R2 expression and regulation.METHODS Ulcerative colitis was induced in mice by administration of 3%(w/v) DSS for 7 d. Once the model was established,mice were administered urocortin-2(30 μg/kg), a peptide which binds exclusively to CRH-R2, or various doses of aqueous TXYF extracts(2.8-11.2 g/kg), a CRH-R2 antagonist Astressin(Ast)2B(20 μg/kg), Ast2B + Ucn2, or Ast2B with various doses of aqueous TXYF extracts for 9 d. Colonic mucosal permeability was then evaluated by measuring the fluorescence intensity in serum. The colitis disease activity index(DAI), histology, body weight loss and colon length were assessed to evaluate the condition of colitis. Terminal deoxynucleotidyl transferase d UTP nick-end labeling was used to detect apoptosis of the intestinal epithelial cells. The expression level of Ki-67 represented the proliferation of colonic epithelial cells and was detected by immunohistochemistry. The expression levels of inflammation cytokines IL-6, TNF-α and CXCL-1 were examined in colon tissues using real-time PCR and ELISA kits.RESULTS Compared with the DSS group, mice treated with the CRH-R2 antagonist Ast2B showed greater loss of body weight, shorter colon lengths(4.90 ± 0.32 vs 6.21 ± 0.34 cm, P < 0.05), and higher DAI(3.61 ± 0.53 vs 2.42 ± 0.32, P < 0.05) and histological scores(11.50 ± 1.05 vs 8.33 ± 1.03, P < 0.05). Additionally, the Ast2B group showed increased intestinal permeability(2.76 ± 0.11 μg/mL vs 1.47 ± 0.11 μg/mL, P < 0.001), improved secretion of inflammatory cytokines in colon tissue, and reduced colonic epithelial cell proliferation(4.97 ± 4.25 vs 22.51 ± 8.22, P < 0.05). Increased apoptosis(1422.39 ± 90.71 vs 983.01 ± 98.17, P < 0.001) was also demonstrated. The Ucn2 group demonstrated lower DAI(0.87 ± 0.55 vs 2.42 ± 0.32, P < 0.001) and histological scores(4.33 ± 1.50 vs 8.33 ± 1.03, P < 0.05). Diminished weight loss, longer colon length(9.58 ± 0.62 vs 6.21 ± 0.34 cm, P < 0.001), reduced intestinal permeability(0.75 ± 0.07 vs 1.47 ± 0.11 μg/mL, P < 0.001), inhibited secretion of inflammatory cytokines in colon tissue and increased colonic epithelial cell proliferation(90.04 ± 15.50 vs 22.51 ± 8.22, P < 0.01) were all observed. Reduced apoptosis(149.55 ± 21.68 vs 983.01 ± 98.17, P < 0.05) was also observed. However, significant statistical differences in the results of the Ast2 B group and Ast2 B + Ucn2 group were observed. TXYF was also found to ameliorate symptoms of DSS-induced colitis in mice and to promote mucosal repair like Ucn2. There were significant differences between the Ast2B + TXYF groups and the TXYF groups.CONCLUSION CRH-R2 activates the intestinal mucosal antiinflammatory response by regulating migration, proliferation and apoptosis of intestinal epithelial cells in colitisinduced mice, and plays an important antiinflammatory role. TXYF promotes mucosal repair in colitis mice by regulating CRH-R2.
AIM To explore the significance of corticotropin-releasing hormone(CRH)-receptor(R)2 in mucosal healing of dextran sulfate sodium(DSS)-induced colitis and the effect of Tong-Xie-Yao-Fang(TXYF) on CRH-R2 expression and regulation.METHODS Ulcerative colitis was induced in mice by administration of 3%(w/v) DSS for 7 d. Once the model was established,mice were administered urocortin-2(30 μg/kg), a peptide which binds exclusively to CRH-R2, or various doses of aqueous TXYF extracts(2.8-11.2 g/kg), a CRH-R2 antagonist Astressin(Ast)2B(20 μg/kg), Ast2B + Ucn2, or Ast2B with various doses of aqueous TXYF extracts for 9 d. Colonic mucosal permeability was then evaluated by measuring the fluorescence intensity in serum. The colitis disease activity index(DAI), histology, body weight loss and colon length were assessed to evaluate the condition of colitis. Terminal deoxynucleotidyl transferase d UTP nick-end labeling was used to detect apoptosis of the intestinal epithelial cells. The expression level of Ki-67 represented the proliferation of colonic epithelial cells and was detected by immunohistochemistry. The expression levels of inflammation cytokines IL-6, TNF-α and CXCL-1 were examined in colon tissues using real-time PCR and ELISA kits.RESULTS Compared with the DSS group, mice treated with the CRH-R2 antagonist Ast2B showed greater loss of body weight, shorter colon lengths(4.90 ± 0.32 vs 6.21 ± 0.34 cm, P < 0.05), and higher DAI(3.61 ± 0.53 vs 2.42 ± 0.32, P < 0.05) and histological scores(11.50 ± 1.05 vs 8.33 ± 1.03, P < 0.05). Additionally, the Ast2B group showed increased intestinal permeability(2.76 ± 0.11 μg/mL vs 1.47 ± 0.11 μg/mL, P < 0.001), improved secretion of inflammatory cytokines in colon tissue, and reduced colonic epithelial cell proliferation(4.97 ± 4.25 vs 22.51 ± 8.22, P < 0.05). Increased apoptosis(1422.39 ± 90.71 vs 983.01 ± 98.17, P < 0.001) was also demonstrated. The Ucn2 group demonstrated lower DAI(0.87 ± 0.55 vs 2.42 ± 0.32, P < 0.001) and histological scores(4.33 ± 1.50 vs 8.33 ± 1.03, P < 0.05). Diminished weight loss, longer colon length(9.58 ± 0.62 vs 6.21 ± 0.34 cm, P < 0.001), reduced intestinal permeability(0.75 ± 0.07 vs 1.47 ± 0.11 μg/mL, P < 0.001), inhibited secretion of inflammatory cytokines in colon tissue and increased colonic epithelial cell proliferation(90.04 ± 15.50 vs 22.51 ± 8.22, P < 0.01) were all observed. Reduced apoptosis(149.55 ± 21.68 vs 983.01 ± 98.17, P < 0.05) was also observed. However, significant statistical differences in the results of the Ast2 B group and Ast2 B + Ucn2 group were observed. TXYF was also found to ameliorate symptoms of DSS-induced colitis in mice and to promote mucosal repair like Ucn2. There were significant differences between the Ast2B + TXYF groups and the TXYF groups.CONCLUSION CRH-R2 activates the intestinal mucosal antiinflammatory response by regulating migration, proliferation and apoptosis of intestinal epithelial cells in colitisinduced mice, and plays an important antiinflammatory role. TXYF promotes mucosal repair in colitis mice by regulating CRH-R2.
AIM To explore the significance of corticotropin-releasing hormone(CRH)-receptor(R)2 in mucosal healing of dextran sulfate sodium(DSS)-induced colitis and the effect of Tong-Xie-Yao-Fang(TXYF) on CRH-R2 expression and regulation.METHODS Ulcerative colitis was induced in mice by administration of 3%(w/v) DSS for 7 d. Once the model was established,mice were administered urocortin-2(30 μg/kg), a peptide which binds exclusively to CRH-R2, or various doses of aqueous TXYF extracts(2.8-11.2 g/kg), a CRH-R2 antagonist Astressin(Ast)2B(20 μg/kg), Ast2B + Ucn2, or Ast2B with various doses of aqueous TXYF extracts for 9 d. Colonic mucosal permeability was then evaluated by measuring the fluorescence intensity in serum. The colitis disease activity index(DAI), histology, body weight loss and colon length were assessed to evaluate the condition of colitis. Terminal deoxynucleotidyl transferase d UTP nick-end labeling was used to detect apoptosis of the intestinal epithelial cells. The expression level of Ki-67 represented the proliferation of colonic epithelial cells and was detected by immunohistochemistry. The expression levels of inflammation cytokines IL-6, TNF-α and CXCL-1 were examined in colon tissues using real-time PCR and ELISA kits.RESULTS Compared with the DSS group, mice treated with the CRH-R2 antagonist Ast2B showed greater loss of body weight, shorter colon lengths(4.90 ± 0.32 vs 6.21 ± 0.34 cm, P < 0.05), and higher DAI(3.61 ± 0.53 vs 2.42 ± 0.32, P < 0.05) and histological scores(11.50 ± 1.05 vs 8.33 ± 1.03, P < 0.05). Additionally, the Ast2B group showed increased intestinal permeability(2.76 ± 0.11 μg/mL vs 1.47 ± 0.11 μg/mL, P < 0.001), improved secretion of inflammatory cytokines in colon tissue, and reduced colonic epithelial cell proliferation(4.97 ± 4.25 vs 22.51 ± 8.22, P < 0.05). Increased apoptosis(1422.39 ± 90.71 vs 983.01 ± 98.17, P < 0.001) was also demonstrated. The Ucn2 group demonstrated lower DAI(0.87 ± 0.55 vs 2.42 ± 0.32, P < 0.001) and histological scores(4.33 ± 1.50 vs 8.33 ± 1.03, P < 0.05). Diminished weight loss, longer colon length(9.58 ± 0.62 vs 6.21 ± 0.34 cm, P < 0.001), reduced intestinal permeability(0.75 ± 0.07 vs 1.47 ± 0.11 μg/mL, P < 0.001), inhibited secretion of inflammatory cytokines in colon tissue and increased colonic epithelial cell proliferation(90.04 ± 15.50 vs 22.51 ± 8.22, P < 0.01) were all observed. Reduced apoptosis(149.55 ± 21.68 vs 983.01 ± 98.17, P < 0.05) was also observed. However, significant statistical differences in the results of the Ast2 B group and Ast2 B + Ucn2 group were observed. TXYF was also found to ameliorate symptoms of DSS-induced colitis in mice and to promote mucosal repair like Ucn2. There were significant differences between the Ast2B + TXYF groups and the TXYF groups.CONCLUSION CRH-R2 activates the intestinal mucosal antiinflammatory response by regulating migration, proliferation and apoptosis of intestinal epithelial cells in colitisinduced mice, and plays an important antiinflammatory role. TXYF promotes mucosal repair in colitis mice by regulating CRH-R2.
引文
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2 Jin F L,Yi-Ping L I.Progress in the traditional Chinese medicine treatment of ulcerative colitis.China Modern Medicine 2016
3 Ouyang Q,Xue LY.Inflammatory bowel disease in the 21(st)century in China:turning challenges into opportunities.JDig Dis 2012;13:195-199[PMID:22435503 DOI:10.1111/j.1751-2980.2012.00579.x]
4 Bernstein CN,Loftus EV Jr,Ng SC,Lakatos PL,Moum B;Epidemiology and Natural History Task Force of the International Organization for the Study of Inflammatory Bowel Disease(IOIBD).Hospitalisations and surgery in Crohn’s disease.Gut 2012;61:622-629[PMID:22267595 DOI:10.1136/gutjnl-2011-301397]
5 Magro F,Rodrigues A,Vieira AI,Portela F,Cremers I,Cotter J,Correia L,Duarte MA,Tavares ML,Lago P,Ministro P,Peixe P,Lopes S,Garcia EB.Review of the disease course among adult ulcerative colitis population-based longitudinal cohorts.Inflamm Bowel Dis 2012;18:573-583[PMID:21793126 DOI:10.1002/ibd.21815]
6 Baars JE,Nuij VJ,Oldenburg B,Kuipers EJ,van der Woude CJ.Majority of patients with inflammatory bowel disease in clinical remission have mucosal inflammation.Inflamm Bowel Dis 2012;18:1634-1640[PMID:22069022 DOI:10.1002/ibd.21925]
7 van Dullemen HM,van Deventer SJ,Hommes DW,Bijl HA,Jansen J,Tytgat GN,Woody J.Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody(c A2).Gastroenterology 1995;109:129-135[PMID:7797011 DOI:10.1016/0016-5085(95)90277-5]
8 Rutgeerts P,D’Haens G,Targan S,Vasiliauskas E,Hanauer SB,Present DH,Mayer L,Van Hogezand RA,Braakman T,De Woody KL,Schaible TF,Van Deventer SJ.Efficacy and safety of retreatment with anti-tumor necrosis factor antibody(infliximab)to maintain remission in Crohn’s disease.Gastroenterology1999;117:761-769[PMID:10500056 DOI:10.1016/S0016-5085(99)70332-X]
9 Rutgeerts P,Diamond RH,Bala M,Olson A,Lichtenstein GR,Bao W,Patel K,Wolf DC,Safdi M,Colombel JF,Lashner B,Hanauer SB.Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease.Gastrointest Endosc2006;63:433-442;quiz 464[PMID:16500392 DOI:10.1016/j.gie.2005.08.011]
10 Hanauer SB,Feagan BG,Lichtenstein GR,Mayer LF,Schreiber S,Colombel JF,Rachmilewitz D,Wolf DC,Olson A,Bao W,Rutgeerts P;ACCENT I Study Group.Maintenance infliximab for Crohn’s disease:the ACCENT I randomised trial.Lancet2002;359:1541-1549[PMID:12047962 DOI:10.1016/S0140-6736(02)08512-4]
11 Sands BE,Anderson FH,Bernstein CN,Chey WY,Feagan BG,Fedorak RN,Kamm MA,Korzenik JR,Lashner BA,Onken JE,Rachmilewitz D,Rutgeerts P,Wild G,Wolf DC,Marsters PA,Travers SB,Blank MA,van Deventer SJ.Infliximab maintenance therapy for fistulizing Crohn’s disease.N Engl J Med 2004;350:876-885[PMID:14985485 DOI:10.1056/NEJMoa030815]
12 R?mkens TE,Gijsbers K,Kievit W,Hoentjen F,Drenth JP.Treatment Targets in Inflammatory Bowel Disease:Current Status in Daily Practice.J Gastrointestin Liver Dis 2016;25:465-471[PMID:27981302 DOI:10.15403/jgld.2014.1121.254.ken]
13 Taupin D,Podolsky DK.Trefoil factors:initiators of mucosal healing.Nat Rev Mol Cell Biol 2003;4:721-732[PMID:14506475DOI:10.1038/nrm1203]
14 Sturm A,Dignass AU.Epithelial restitution and wound healing in inflammatory bowel disease.World J Gastroenterol 2008;14:348-353[PMID:18200658 DOI:10.3748/wjg.14.348]
15 Neurath MF.New targets for mucosal healing and therapy in inflammatory bowel diseases.Mucosal Immunol 2014;7:6-19[PMID:24084775 DOI:10.1038/mi.2013.73]
16 Neurath MF,Travis SP.Mucosal healing in inflammatory bowel diseases:a systematic review.Gut 2012;61:1619-1635[PMID:22842618 DOI:10.1136/gutjnl-2012-302830]
17 Laukoetter MG,Nava P,Nusrat A.Role of the intestinal barrier in inflammatory bowel disease.World J Gastroenterol 2008;14:401-407[PMID:18200662]
18 Giannogonas P,Apostolou A,Manousopoulou A,Theocharis S,Macari SA,Psarras S,Garbis SD,Pothoulakis C,Karalis KP.Identification of a novel interaction between corticotropin releasing hormone(Crh)and macroautophagy.Sci Rep 2016;6:23342[PMID:26987580 DOI:10.1038/srep23342]
19 Bonaz BL,Bernstein CN.Brain-gut interactions in inflammatory bowel disease.Gastroenterology 2013;144:36-49[PMID:23063970 DOI:10.1053/j.gastro.2012.10.003]
20 Hillhouse EW,Grammatopoulos DK.The molecular mechanisms underlying the regulation of the biological activity of corticotropinreleasing hormone receptors:implications for physiology and pathophysiology.Endocr Rev 2006;27:260-286[PMID:16484629DOI:10.1210/er.2005-0034]
21 Hoffman JM,Baritaki S,Ruiz JJ,Sideri A,Pothoulakis C.Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis.Am J Pathol 2016;186:134-144[PMID:26597886 DOI:10.1016/j.ajpath.2015.09.013]
22 Wang X T,Hu Y,Li M,Lv B.Study on the role of stress through CRF up regulation of CK8 mediated change of close connexin in the pathogenesis of irritable bowel syndrome.The national association of Chinese and western medicine on digestive system disease academic conference,2015
23 Im E,Rhee SH,Park YS,Fiocchi C,TachéY,Pothoulakis C.Corticotropin-releasing hormone family of peptides regulates intestinal angiogenesis.Gastroenterology 2010;138:2457-2467,2467.e1-2467.e5[PMID:20206175 DOI:10.1053/j.gastro.2010.02.055]
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