Efi Kokkotou

OBJECTIVE: To investigate whether placebo effects can experimentally be separated into the response to three components-assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship-and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components. DESIGN: A six week single blind three arm randomised controlled trial. SETTING: Academic medical centre. PARTICIPANTS: 262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of > or =150 on the symptom severity scale. INTERVENTIONS: For three weeks either waiting list (observation), placebo acupuncture alone ("limited"), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence ("augmented"). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks. MAIN OUTCOME MEASURES: Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life. RESULTS: At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus "limited" versus "augmented," respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01). Results were similar at six week follow-up. CONCLUSION: Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component. TRIAL REGISTRATION: Clinical Trials NCT00065403.

BACKGROUND: Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS). METHODS: Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47 ± 18 with IBS diagnosed by Rome III criteria and with a score ≥ 150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as "placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes" or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL). FINDINGS: Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2 ± 1.0 vs. 4.0 ± 1.1, p<.001) and at 21-day endpoint (5.0 ± 1.5 vs. 3.9 ± 1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08). CONCLUSION: Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent. TRIAL REGISTRATION: ClinicalTrials.gov NCT01010191.

Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity.

Intestinal fibrosis is a major complication of Crohn disease (CD), but the precise mechanism by which it occurs is incompletely understood. As a result, specific therapies to halt or even reverse fibrosis have not been explored. Here, we evaluated the contribution of epithelial to mesenchymal transition (EMT) to intestinal fibrosis associated with a mouse model of CD and also human inflammatory bowel disease. Mice administered intrarectal 2,4,6-trinitrobenzene sulfonic acid (TNBS) develop inflammation and fibrosis that resembles CD both histologically and by immunologic profile. We utilized this model to molecularly probe the contribution of EMT to intestinal fibrosis. Additionally, we utilized double-transgenic VillinCre;R26Rosa-lox-STOP-lox-LacZ mice, in which removal of the STOP cassette by Cre recombinase in villin+ intestinal epithelial cells activates permanent LacZ expression, to lineage trace epithelial cells that might undergo EMT upon TNBS administration. TNBS-induced fibrosis is associated with the presence of a significant number of cells that express both epithelial and mesenchymal markers. In the lineage tagged transgenic mice, the appearance of LacZ+ cells that also express the fibroblast marker FSP1 unequivocally demonstrates EMT. Transforming growth factor (TGF)-β1, a known inducer of EMT in epithelial cells, induces EMT in rat intestinal epithelial cells in vitro, and bone morphogenic protein-7, an antagonist of TGF-β1, inhibits EMT and fibrosis both in vitro and in the TNBS-treated mice. Our study demonstrates that EMT contributes to intestinal fibrosis associated with the TNBS-induced model of Crohn colitis and that inhibition of TGF-β1 with recombinant human bone morphogenic protein-7 prevents this process and prevents fibrosis. Intestinal fibrosis is a major complication of Crohn disease (CD), but the precise mechanism by which it occurs is incompletely understood. As a result, specific therapies to halt or even reverse fibrosis have not been explored. Here, we evaluated the contribution of epithelial to mesenchymal transition (EMT) to intestinal fibrosis associated with a mouse model of CD and also human inflammatory bowel disease. Mice administered intrarectal 2,4,6-trinitrobenzene sulfonic acid (TNBS) develop inflammation and fibrosis that resembles CD both histologically and by immunologic profile. We utilized this model to molecularly probe the contribution of EMT to intestinal fibrosis. Additionally, we utilized double-transgenic VillinCre;R26Rosa-lox-STOP-lox-LacZ mice, in which removal of the STOP cassette by Cre recombinase in villin+ intestinal epithelial cells activates permanent LacZ expression, to lineage trace epithelial cells that might undergo EMT upon TNBS administration. TNBS-induced fibrosis is associated with the presence of a significant number of cells that express both epithelial and mesenchymal markers. In the lineage tagged transgenic mice, the appearance of LacZ+ cells that also express the fibroblast marker FSP1 unequivocally demonstrates EMT. Transforming growth factor (TGF)-β1, a known inducer of EMT in epithelial cells, induces EMT in rat intestinal epithelial cells in vitro, and bone morphogenic protein-7, an antagonist of TGF-β1, inhibits EMT and fibrosis both in vitro and in the TNBS-treated mice. Our study demonstrates that EMT contributes to intestinal fibrosis associated with the TNBS-induced model of Crohn colitis and that inhibition of TGF-β1 with recombinant human bone morphogenic protein-7 prevents this process and prevents fibrosis. IntroductionCrohn disease (CD) 5The abbreviations used are: CDCrohn diseaseα-SMAα-smooth muscle actinEMTepithelial to mesenchymal transitionFSP1fibroblast-specific protein 1MTSMasson trichrome stainrhBMP-7recombinant human bone morphogenic protein-7RStopLacZR26-lox-Stop-lox-LacZTGF-βtransforming growth factor-βTNBS2,4,6-trinitrobenzene sulfonic acidTNF-αtumor necrosis factor-αVillin-LacZVillinCre;R26Rosa-lox-Stop-lox-LacZDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serumDAPI4′,6-diamidino-2-phenylindoleH&Ehematoxylin and eosinβ-galβ-galactosidase. is a disorder of chronic, transmural inflammation that can affect any part of the gastrointestinal tract from the mouth to the anus (1Podolsky D.K. N. Engl. J. Med. 2002; 347: 417-429Crossref PubMed Scopus (3128) Google Scholar, 2Fiocchi C. Gastroenterology. 1998; 115: 182-205Abstract Full Text Full Text PDF PubMed Scopus (1855) Google Scholar). Chronic inflammation combined with dysregulated wound healing is thought to result in a number of complications including fistula and fibrostenotic stricture formation (3Froehlich F. Juillerat P. Mottet C. Pittet V. Felley C. Vader J.P. Gonvers J.J. Michetti P. Digestion. 2007; 76: 113-115Crossref PubMed Scopus (19) Google Scholar, 4Rieder F. Brenmoehl J. Leeb S. Schölmerich J. Rogler G. Gut. 2007; 56: 130-139Crossref PubMed Scopus (230) Google Scholar). Over one-third of patients with CD undergo surgery to relieve obstruction related to fibrotic strictures, and many will require repeat interventions because of recurrent disease (3Froehlich F. Juillerat P. Mottet C. Pittet V. Felley C. Vader J.P. Gonvers J.J. Michetti P. Digestion. 2007; 76: 113-115Crossref PubMed Scopus (19) Google Scholar).As with fibrosis in other organ systems, intestinal fibrosis is considered to follow a common pathway of fibrogenesis (4Rieder F. Brenmoehl J. Leeb S. Schölmerich J. Rogler G. Gut. 2007; 56: 130-139Crossref PubMed Scopus (230) Google Scholar, 5Pucilowska J.B. Williams K.L. Lund P.K. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 279: G653-G659Crossref PubMed Google Scholar). In what is presumably a protective adaptation, activated fibroblasts are recruited to sites of severe inflammation for the purpose of wound healing. Although fibroblasts are considered a heterogeneous population (6Kalluri R. Zeisberg M. Nat. Rev. Cancer. 2006; 6: 392-401Crossref PubMed Scopus (3468) Google Scholar, 7Sugimoto H. Mundel T.M. Kieran M.W. Kalluri R. Cancer Biol. Ther. 2006; 5: 1640-1646Crossref PubMed Scopus (517) Google Scholar), those that express fibroblast-specific protein 1 (FSP1) or α-smooth muscle actin (α-SMA) are the main types mediating fibrosis (8Strutz F. Zeisberg M. J. Am. Soc. Nephrol. 2006; 17: 2992-2998Crossref PubMed Scopus (265) Google Scholar, 9Strutz F. Okada H. Lo C.W. Danoff T. Carone R.L. Tomaszewski J.E. Neilson E.G. J. Cell Biol. 1995; 130: 393-405Crossref PubMed Scopus (877) Google Scholar, 10Okada H. Danoff T.M. Kalluri R. Neilson E.G. Am. J. Physiol. 1997; 273: F563-F574Crossref PubMed Google Scholar). With persistent inflammation, fibrosis may result from excessive deposition of the extracellular matrix (4Rieder F. Brenmoehl J. Leeb S. Schölmerich J. Rogler G. Gut. 2007; 56: 130-139Crossref PubMed Scopus (230) Google Scholar, 5Pucilowska J.B. Williams K.L. Lund P.K. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 279: G653-G659Crossref PubMed Google Scholar, 11Schuppan D. Ruehl M. Somasundaram R. Hahn E.G. Semin. Liver Dis. 2001; 21: 351-372Crossref PubMed Scopus (428) Google Scholar, 12Friedman S.L. J. Biol. Chem. 2000; 275: 2247-2250Abstract Full Text Full Text PDF PubMed Scopus (1877) Google Scholar). A better understanding of why and how this happens will likely have a dramatic impact on the treatment of CD and its myriad complications.Epithelial to mesenchymal transition (EMT) is a key contributor to the pool of activated fibroblasts in multiple organ systems including the heart, lung, liver, and kidney (13Kalluri R. Neilson E.G. J. Clin. Invest. 2003; 112: 1776-1784Crossref PubMed Scopus (2061) Google Scholar, 14Zeisberg M. Yang C. Martino M. Duncan M.B. Rieder F. Tanjore H. Kalluri R. J. Biol. Chem. 2007; 282: 23337-23347Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar, 15Kim K.K. Kugler M.C. Wolters P.J. Robillard L. Galvez M.G. Brumwell A.N. Sheppard D. Chapman H.A. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 13180-13185Crossref PubMed Scopus (1002) Google Scholar, 16Iwano M. Plieth D. Danoff T.M. Xue C. Okada H. Neilson E.G. J. Clin. Invest. 2002; 110: 341-350Crossref PubMed Scopus (1698) Google Scholar, 17Zeisberg E.M. Tarnavski O. Zeisberg M. Dorfman A.L. McMullen J.R. Gustafsson E. Chandraker A. Yuan X. Pu W.T. Roberts A.B. Neilson E.G. Sayegh M.H. Izumo S. Kalluri R. Nat. Med. 2007; 13: 952-961Crossref PubMed Scopus (1591) Google Scholar). EMT is a process in which epithelial cells lose their phenotypic and functional characteristics while acquiring mesenchymal features (13Kalluri R. Neilson E.G. J. Clin. Invest. 2003; 112: 1776-1784Crossref PubMed Scopus (2061) Google Scholar, 18Zeisberg M. Kalluri R. J. Mol. Med. 2004; 82: 175-181Crossref PubMed Scopus (423) Google Scholar, 19Kalluri R. Weinberg R.A. J. Clin. Invest. 2009; 119: 1420-1428Crossref PubMed Scopus (7127) Google Scholar, 20Hay E.D. Zuk A. Am. J. Kidney Dis. 1995; 26: 678-690Abstract Full Text PDF PubMed Scopus (353) Google Scholar). The role of EMT in intestinal fibrosis has yet to be investigated.Although organ fibrosis was once considered irreversible, recent data from animal models of renal, hepatic, and cardiac fibrosis demonstrate the anti-fibrotic effect of recombinant human bone morphogenic protein-7 (rhBMP-7) (14Zeisberg M. Yang C. Martino M. Duncan M.B. Rieder F. Tanjore H. Kalluri R. J. Biol. Chem. 2007; 282: 23337-23347Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar, 17Zeisberg E.M. Tarnavski O. Zeisberg M. Dorfman A.L. McMullen J.R. Gustafsson E. Chandraker A. Yuan X. Pu W.T. Roberts A.B. Neilson E.G. Sayegh M.H. Izumo S. Kalluri R. Nat. Med. 2007; 13: 952-961Crossref PubMed Scopus (1591) Google Scholar, 21Zeisberg M. Nephrol. Dial. Transplant. 2006; 21: 568-573Crossref PubMed Scopus (69) Google Scholar, 22Zeisberg M. Hanai J. Sugimoto H. Mammoto T. Charytan D. Strutz F. Kalluri R. Nat. Med. 2003; 9: 964-968Crossref PubMed Scopus (1170) Google Scholar). BMP-7 is a member of the transforming growth factor-β (TGF-β) superfamily and is one of 15 proteins with structural and functional homology (21Zeisberg M. Nephrol. Dial. Transplant. 2006; 21: 568-573Crossref PubMed Scopus (69) Google Scholar, 23Kingsley D.M. Genes Dev. 1994; 8: 133-146Crossref PubMed Scopus (1726) Google Scholar, 24Ducy P. Karsenty G. Kidney Int. 2000; 57: 2207-2214Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar). BMP-7 was first recognized for its regulatory effect on bone and cartilage formation and is currently employed clinically to accelerate fracture healing (25Cook S.D. Rueger D.C. Clin. Orthop. Relat. Res. 1996; 324: 29-38Crossref PubMed Scopus (151) Google Scholar, 26Friedlaender G.E. Perry C.R. Cole J.D. Cook S.D. Cierny G. Muschler G.F. Zych G.A. Calhoun J.H. LaForte A.J. Yin S. J. Bone Joint. Surg. Am. 2001; 83-A: S151-S158Google Scholar). With respect to organ fibrosis, the anti-fibrotic effect of rhBMP-7 stems from its ability to counteract the pro-fibrotic action of TGF-β1 (17Zeisberg E.M. Tarnavski O. Zeisberg M. Dorfman A.L. McMullen J.R. Gustafsson E. Chandraker A. Yuan X. Pu W.T. Roberts A.B. Neilson E.G. Sayegh M.H. Izumo S. Kalluri R. Nat. Med. 2007; 13: 952-961Crossref PubMed Scopus (1591) Google Scholar, 22Zeisberg M. Hanai J. Sugimoto H. Mammoto T. Charytan D. Strutz F. Kalluri R. Nat. Med. 2003; 9: 964-968Crossref PubMed Scopus (1170) Google Scholar), which has been implicated in the fibrosis of various organs including the gut (27Fiocchi C. Am. J. Physiol. 1997; 273: G769-G775PubMed Google Scholar). Receptors for BMP-7 are present on colonocytes (28Grijelmo C. Rodrigue C. Svrcek M. Bruyneel E. Hendrix A. de Wever O. Gespach C. Cell Signal. 2007; 19: 1722-1732Crossref PubMed Scopus (70) Google Scholar), and systemically administered rhBMP-7 binds with high affinity to the inflamed colon and prevents inflammation in a rat model of CD induced by rectally administered 2,4,6-trinitrobenzene sulfonic acid (TNBS) (29Maric I. Poljak L. Zoricic S. Bobinac D. Bosukonda D. Sampath K.T. S. J. Physiol. 2003; PubMed Scopus Google Scholar). The of study was to the contribution of EMT to intestinal fibrosis associated with both a mouse model of Crohn colitis and human inflammatory bowel disease to the the anti-fibrotic of rhBMP-7 in the inflamed fibrosis in the of fibrostenotic is a complication of CD and is thought to a result of inflammation and dysregulated wound healing C. Gastroenterology. 1998; 115: 182-205Abstract Full Text Full Text PDF PubMed Scopus (1855) Google Scholar, F. Juillerat P. Mottet C. Pittet V. Felley C. Vader J.P. Gonvers J.J. Michetti P. Digestion. 2007; 76: 113-115Crossref PubMed Scopus (19) Google Scholar). The mechanism by which inflammation to fibrosis is to be but likely EMT to (13Kalluri R. Neilson E.G. J. Clin. Invest. 2003; 112: 1776-1784Crossref PubMed Scopus (2061) Google Scholar). Although various and have for have impact on fibrosis once it occurs (3Froehlich F. Juillerat P. Mottet C. Pittet V. Felley C. Vader J.P. Gonvers J.J. Michetti P. Digestion. 2007; 76: 113-115Crossref PubMed Scopus (19) Google is a process in which epithelial cells lose their phenotypic and functional characteristics and develop features of the the epithelial and to develop a and R. Weinberg R.A. J. Clin. Invest. 2009; 119: 1420-1428Crossref PubMed Scopus (7127) Google Scholar, E.D. 1995; PubMed Scopus Google for EMT epithelial cells in intestinal fibrosis, we transgenic in which intestinal epithelial cells can be by of colitis in the mice, we to demonstrate for the first that EMT contributes to the pool of activated fibroblasts that in a model of Crohn colitis by treatment with fibroblasts are the main of fibrogenesis in the colon in other organs A. S. M. Ther. 2007; PubMed Scopus Google Scholar, J.D. A.B. Am. J. Physiol. PubMed Google Scholar). are a heterogeneous population (6Kalluri R. Zeisberg M. Nat. Rev. Cancer. 2006; 6: 392-401Crossref PubMed Scopus (3468) Google and the major that are known to fibrosis express FSP1 or (8Strutz F. Zeisberg M. J. Am. Soc. Nephrol. 2006; 17: 2992-2998Crossref PubMed Scopus (265) Google Scholar). fibroblasts have been the fibrogenesis of liver, and (14Zeisberg M. Yang C. Martino M. Duncan M.B. Rieder F. Tanjore H. Kalluri R. J. Biol. Chem. 2007; 282: 23337-23347Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar, 16Iwano M. Plieth D. Danoff T.M. Xue C. Okada H. Neilson E.G. J. Clin. Invest. 2002; 110: 341-350Crossref PubMed Scopus (1698) Google Scholar, 17Zeisberg E.M. Tarnavski O. Zeisberg M. Dorfman A.L. McMullen J.R. Gustafsson E. Chandraker A. Yuan X. Pu W.T. Roberts A.B. Neilson E.G. Sayegh M.H. Izumo S. Kalluri R. Nat. Med. 2007; 13: 952-961Crossref PubMed Scopus (1591) Google and from EMT M. Kalluri R. J. Mol. Med. 2004; 82: 175-181Crossref PubMed Scopus (423) Google Scholar). In model of the of both and fibroblasts upon disease The effect of treatment with TNBS is dramatic on the population of fibroblasts we used this marker for that one-third of fibroblasts are from intestinal epithelial result is with of EMT in mouse models of M. Kalluri R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and (14Zeisberg M. Yang C. Martino M. Duncan M.B. Rieder F. Tanjore H. Kalluri R. J. Biol. Chem. 2007; 282: 23337-23347Abstract Full Text Full Text PDF PubMed Scopus (651) Google fibrosis but may be an because the LacZ is in of the Although FSP1 is to epithelial cells that have a fibroblast and of epithelial data the that EMT occurs in the model of TNBS-induced intestinal the anti-fibrotic of rhBMP-7 in this model of a of TNBS with As we and have BMP-7 its anti-fibrotic action in the of disease of the liver, and inhibition of EMT (14Zeisberg M. Yang C. Martino M. Duncan M.B. Rieder F. Tanjore H. Kalluri R. J. Biol. Chem. 2007; 282: 23337-23347Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar, 17Zeisberg E.M. Tarnavski O. Zeisberg M. Dorfman A.L. McMullen J.R. Gustafsson E. Chandraker A. Yuan X. Pu W.T. Roberts A.B. Neilson E.G. Sayegh M.H. Izumo S. Kalluri R. Nat. Med. 2007; 13: 952-961Crossref PubMed Scopus (1591) Google Scholar, 22Zeisberg M. Hanai J. Sugimoto H. Mammoto T. Charytan D. Strutz F. Kalluri R. Nat. Med. 2003; 9: 964-968Crossref PubMed Scopus (1170) Google Scholar). we that to the pool of fibroblasts in the of intestinal fibrosis and that inhibition of EMT by rhBMP-7 fibrosis. of rhBMP-7 in with TNBS the epithelial and fibrosis in the with have that the TNBS-induced model of Crohn colitis is associated with (29Maric I. Poljak L. Zoricic S. Bobinac D. Bosukonda D. Sampath K.T. S. J. Physiol. 2003; PubMed Scopus Google that of rhBMP-7 its anti-fibrotic action of a pathway in which colonocytes a role (29Maric I. Poljak L. Zoricic S. Bobinac D. Bosukonda D. Sampath K.T. S. J. Physiol. 2003; PubMed Scopus Google Scholar). Our not the that other are to intestinal fibrosis. In this and have been to be in the colon in to BMP-7 L. H. S. D.C. J. Clin. Invest. 2006; PubMed Scopus Google Scholar, C. J. C. X. Proc. Natl. Acad. Sci. U.S.A. 2007; PubMed Scopus Google is associated with a of effect of on TGF-β1 S. C. J. Med. 2007; PubMed Scopus Google Scholar). In this demonstrate that TGF-β1 is a inducer of EMT and that BMP-7 inhibits EMT even while are to of the of and rhBMP-7 in the of inflammation and fibrosis in Although is that treatment with an may stricture formation in patients A. S. D.M. Am. J. 2006; PubMed Scopus Google Scholar, D. G. S. C. Digestion. 2007; PubMed Scopus (19) Google Scholar). In treatment may be and is a of intestinal fibrosis (4Rieder F. Brenmoehl J. Leeb S. Schölmerich J. Rogler G. Gut. 2007; 56: 130-139Crossref PubMed Scopus (230) Google Scholar), and it is the inducer of EMT in various organ systems (13Kalluri R. Neilson E.G. J. Clin. Invest. 2003; 112: 1776-1784Crossref PubMed Scopus (2061) Google Scholar). we the of TGF-β1 to EMT in rat intestinal epithelial The in in the treatment with TNBS to a inflammatory process that resembles CD both in and S. C. Nat. 2007; PubMed Scopus Google Scholar, M. I. Int. Rev. 2000; 19: PubMed Scopus Google Scholar, F. 2002; Google Scholar), the role of EMT in human inflammatory bowel disease A recent a role for EMT in from a of patients with CD F. C. R. A. Rieder F. Brenmoehl J. S. A. F. Schölmerich J. H. Rogler G. Dis. PubMed Scopus Google Scholar). Our of and in intestinal from patients with inflammatory bowel disease that EMT likely occurs in human intestinal fibrosis The of from patients with CD and colitis the of of human data a role for EMT in human inflammatory bowel disease. the are to CD or a result of inflammation associated with any number of to be of in a and will be to this process it to human intestinal fibrosis in and CD in study demonstrates a role for EMT in the of TNBS-induced intestinal fibrosis. As has been in the kidney and heart, treatment with rhBMP-7 both in and in vitro prevents EMT associated with fibrosis. that rhBMP-7 may be an for intestinal fibrosis in and CD in IntroductionCrohn disease (CD) 5The abbreviations used are: CDCrohn diseaseα-SMAα-smooth muscle actinEMTepithelial to mesenchymal transitionFSP1fibroblast-specific protein 1MTSMasson trichrome stainrhBMP-7recombinant human bone morphogenic protein-7RStopLacZR26-lox-Stop-lox-LacZTGF-βtransforming growth factor-βTNBS2,4,6-trinitrobenzene sulfonic acidTNF-αtumor necrosis factor-αVillin-LacZVillinCre;R26Rosa-lox-Stop-lox-LacZDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serumDAPI4′,6-diamidino-2-phenylindoleH&Ehematoxylin and eosinβ-galβ-galactosidase. is a disorder of chronic, transmural inflammation that can affect any part of the gastrointestinal tract from the mouth to the anus (1Podolsky D.K. N. Engl. J. Med. 2002; 347: 417-429Crossref PubMed Scopus (3128) Google Scholar, 2Fiocchi C. Gastroenterology. 1998; 115: 182-205Abstract Full Text Full Text PDF PubMed Scopus (1855) Google Scholar). Chronic inflammation combined with dysregulated wound healing is thought to result in a number of complications including fistula and fibrostenotic stricture formation (3Froehlich F. Juillerat P. Mottet C. Pittet V. Felley C. Vader J.P. Gonvers J.J. Michetti P. Digestion. 2007; 76: 113-115Crossref PubMed Scopus (19) Google Scholar, 4Rieder F. Brenmoehl J. Leeb S. Schölmerich J. Rogler G. Gut. 2007; 56: 130-139Crossref PubMed Scopus (230) Google Scholar). Over one-third of patients with CD undergo surgery to relieve obstruction related to fibrotic strictures, and many will require repeat interventions because of recurrent disease (3Froehlich F. Juillerat P. Mottet C. Pittet V. Felley C. Vader J.P. Gonvers J.J. Michetti P. Digestion. 2007; 76: 113-115Crossref PubMed Scopus (19) Google Scholar).As with fibrosis in other organ systems, intestinal fibrosis is considered to follow a common pathway of fibrogenesis (4Rieder F. Brenmoehl J. Leeb S. Schölmerich J. Rogler G. Gut. 2007; 56: 130-139Crossref PubMed Scopus (230) Google Scholar, 5Pucilowska J.B. Williams K.L. Lund P.K. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 279: G653-G659Crossref PubMed Google Scholar). In what is presumably a protective adaptation, activated fibroblasts are recruited to sites of severe inflammation for the purpose of wound healing. Although fibroblasts are considered a heterogeneous population (6Kalluri R. Zeisberg M. Nat. Rev. Cancer. 2006; 6: 392-401Crossref PubMed Scopus (3468) Google Scholar, 7Sugimoto H. Mundel T.M. Kieran M.W. Kalluri R. Cancer Biol. Ther. 2006; 5: 1640-1646Crossref PubMed Scopus (517) Google Scholar), those that express fibroblast-specific protein 1 (FSP1) or α-smooth muscle actin (α-SMA) are the main types mediating fibrosis (8Strutz F. Zeisberg M. J. Am. Soc. Nephrol. 2006; 17: 2992-2998Crossref PubMed Scopus (265) Google Scholar, 9Strutz F. Okada H. Lo C.W. Danoff T. Carone R.L. Tomaszewski J.E. Neilson E.G. J. Cell Biol. 1995; 130: 393-405Crossref PubMed Scopus (877) Google Scholar, 10Okada H. Danoff T.M. Kalluri R. Neilson E.G. Am. J. Physiol. 1997; 273: F563-F574Crossref PubMed Google Scholar). With persistent inflammation, fibrosis may result from excessive deposition of the extracellular matrix (4Rieder F. Brenmoehl J. Leeb S. Schölmerich J. Rogler G. Gut. 2007; 56: 130-139Crossref PubMed Scopus (230) Google Scholar, 5Pucilowska J.B. Williams K.L. Lund P.K. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 279: G653-G659Crossref PubMed Google Scholar, 11Schuppan D. Ruehl M. Somasundaram R. Hahn E.G. 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