BACKGROUND: Glucocorticoids and monoclonal antibodies to tumor necrosis factor reduce inflammation in Crohn's disease (CD). Rapid luminal healing, however, may promote intestinal stricture formation. The aim of this study was to examine fibrosis-associated gene expression in the intestine of patients with CD and correlate expression levels with prior medical therapies. METHODS: In all, 37 patients with stricturing CD and 18 non-CD controls underwent a transmural biopsy at the time of elective intestinal resection. Quantitative real-time polymerase chain reaction (PCR) was conducted to determine differential mRNA expression of TGF-beta(1), Smad-7, CTGF, collagen-1alpha, fibronectin, BMP-7, and MIF. Intestinal fibroblasts were treated in vitro with dexamethasone. RESULTS: Relative to control, strictured CD intestinal tissue expressed increased TGF-beta(1), CTGF, collagen-1alpha, and BMP-7 (all P < 0.05). TGF-beta(1) gene expression positively correlated with the expression of its downstream targets (all P < 0.001). Preoperative infliximab exposure was not associated with increased expression in any of the target genes nor did the number of infliximab infusions correlate with gene expression. The number of cycles of corticosteroid treatment preoperatively was positively associated with CTGF (r = 0.486, P = 0.016) and MIF (r = 0.524, P = 0.009) expression. Intestinal fibroblasts treated in vitro with dexamethasone upregulated CTGF expression (P = 0.023). CONCLUSIONS: Exposure to infliximab does not appear to induce a profibrotic transcriptional response in the CD intestine. Previous corticosteroid treatment is associated with increased expression of CTGF and MIF. Treating intestinal fibroblasts in vitro with steroids upregulates CTGF expression.
BACKGROUND: Glucocorticoids and monoclonal antibodies to tumor necrosis factor reduce inflammation in Crohn's disease (CD). Rapid luminal healing, however, may promote intestinal stricture formation. The aim of this study was to examine fibrosis-associated gene expression in the intestine of patients with CD and correlate expression levels with prior medical therapies. METHODS: In all, 37 patients with stricturing CD and 18 non-CD controls underwent a transmural biopsy at the time of elective intestinal resection. Quantitative real-time polymerase chain reaction (PCR) was conducted to determine differential mRNA expression of TGF-beta(1), Smad-7, CTGF, collagen-1alpha, fibronectin, BMP-7, and MIF. Intestinal fibroblasts were treated in vitro with dexamethasone. RESULTS: Relative to control, strictured CD intestinal tissue expressed increased TGF-beta(1), CTGF, collagen-1alpha, and BMP-7 (all P < 0.05). TGF-beta(1) gene expression positively correlated with the expression of its downstream targets (all P < 0.001). Preoperative infliximab exposure was not associated with increased expression in any of the target genes nor did the number of infliximab infusions correlate with gene expression. The number of cycles of corticosteroid treatment preoperatively was positively associated with CTGF (r = 0.486, P = 0.016) and MIF (r = 0.524, P = 0.009) expression. Intestinal fibroblasts treated in vitro with dexamethasone upregulated CTGF expression (P = 0.023). CONCLUSIONS: Exposure to infliximab does not appear to induce a profibrotic transcriptional response in the CD intestine. Previous corticosteroid treatment is associated with increased expression of CTGF and MIF. Treating intestinal fibroblasts in vitro with steroids upregulates CTGF expression.
Authors: Chao Li; Audra Iness; Jennifer Yoon; John R Grider; Karnam S Murthy; John M Kellum; John F Kuemmerle Journal: J Immunol Date: 2015-03-04 Impact factor: 5.422
Authors: Chao Li; Robert S Flynn; John R Grider; Karnam S Murthy; John M Kellum; Homayoon Akbari; John F Kuemmerle Journal: Inflamm Bowel Dis Date: 2013-12 Impact factor: 5.325
Authors: Keith W McLarren; Alexandra E Cole; Shelley B Weisser; Nicole S Voglmaier; Victoria S Conlin; Kevan Jacobson; Oana Popescu; Jean-Luc Boucher; Laura M Sly Journal: Am J Pathol Date: 2011-05-07 Impact factor: 4.307