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Role of TGF-Beta1 and IGF-1 in Crohn’S Disease Recurrence After Ileo-Colonic Resection
Marco Scarpa1, Marina Bortolami2, Susan L. Morgan3, Andromachi Kotsafti2, Stefania Ferraro1, Cesare Ruffolo1, Renata D'Incà2, Lino Polese1, Michela Barollo2, Davide F. D'Amico1, Giacomo C. Sturniolo2, Imerio Angriman*1
1Clinica Chirurgica I, Dipartimento di Scienze Chirurgiche e Gastroenterologiche, University of Padova, Padova, Italy; 2Gastroenterologia, Dipartimento di Scienze Chirurgiche e Gastroenterologiche, University of Padova, Padova, Italy; 3Department of Pathology, Institute for Cancer Studies, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom

Background
One of the most challenging problems in the surgical treatment of Crohn’s disease (CD) is the high frequency of recurrence after resection of the affected bowel. Alteration of normal healing processes may play a role in this phenomenon. Transforming growth factor beta (TGF-beta) is universally involved in organ fibrosis and insulin-like growth factor (IGF-I) is involved in chronic inflammation and wound healing mechanisms with pro-fibrogenic properties.
Patients and methods
Twenty patients affected by CD who underwent ileo-colonic resection in our department, over the period 1999 to 2005, were enrolled in this study and their follow up investigated. Tissue samples were obtained from macroscopically diseased and healthy ileum. The TGF-beta1 and IGF-1 mRNAs were quantified by absolute Real Time PCR using GAPDH as the housekeeping gene. Myeloperoxidase (MPO) activity and histological disease activity were assessed to quantify the ileal inflammation. Comparisons and correlations were carried out with nonparametric tests and survival analysis was performed.
Results
Histological inflammation was medially severe in diseased bowel and remission in healthy bowel (p<0.01). Histological activity in healthy bowel correlated with clinical CD recurrence (tau=0.48, p=0.03) but survival analysis did not confirm this association. On the contrary TGF-beta1 in healthy bowel showed a direct correlation with clinical CD recurrence (tau=0.43, p=0.04) and survival analysis showed that patients who expressed high TGF-beta1 mRNA transcripts in healthy bowel had higher cumulative recurrence rates than patients who expressed low TGF-beta1 mRNA levels (p=0.02). IGF-1 mRNA transcripts in healthy bowel were significantly lower in patients who had post operative intestinal complications (p=0.05). IGF-1 mRNA transcripts in healthy bowel correlated inversely with CRP serum levels (tau=-0.51, p=0.04).

Conclusion
Our study seems to show that in patients who undergo ileo-colonic resection for CD the high levels of TGF-beta1 mRNA expression in healthy bowel are associated with early clinical recurrence of CD. In healthy bowel, low IGF-1 expression in patients who experienced post operative intestinal complications associated to the inverse correlation between IGF-1 and CRP seems to suggest that the IL-6-mediated inhibition of IGF-1 might be the molecular connection between severe CD and wound-repairing mechanism failure.


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