Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis.

BACKGROUND AND AIMS: The stiffening of the extracellular matrix, and changes in its cellular and molecular composition, have been reported in the pathogenesis of fibrosis. We analyze the mechanisms that perpetuate ileal fibrosis in surgical resections of complicated Crohn's disease patients. METHODS: Ileal resections were obtained from affected and non-affected tissue of stenotic or penetrating Crohn's disease behavior. Ilea from non-IBD patients were used as control tissue. All samples underwent RNA sequencing. Human small intestinal fibroblasts were treated for 48 h with IL-1ß, TFGß1, PDGFB or TNF-α. Resistance to apoptosis was analysed by RT-PCR, western blot and immunohistochemistry in ileal tissue and by RT-PCR and FACS in cultured cells. RESULTS: Growth factor-driven signaling pathways and increased RAS GTPase activity were up-regulated in affected ilea in which we found expression of both the antiapoptotic molecule MCL1 and the transcription factor ETS1 in submucosal fibroblasts, and a senescence-associated secretory phenotype. In cultured intestinal fibroblasts, PDGFB induced an ETS1-mediated resistance to apoptosis that was associated with the induction of both of TGFB1 and IL1B, a cytokine that replicated the expression of SASP detected in ileal tissue. ETS1 drove fibroblast polarization between inflammatory and fibrogenic phenotypes in IL1ß-treated cells. CONCLUSIONS: Our data show resistance to apoptosis in complicated ileal CD, and demonstrate that PDGFB induce an ETS1-mediated resistance to apoptosis associated with an inflammatory and fibrogenic pattern of expression in intestinal fibroblasts. Results point to PDGFRB, IL1R1 or MCL1 as potential targets against ileal fibrosis.

Prospective evaluation of intraoperative peripheral nerve injury in colorectal surgery.

AIM: Intraoperative peripheral nerve injury can have permanent neurological consequences. Its incidence is not known and varies according to the location and the surgical specialty. This study was a prospective analysis of intraoperative peripheral nerve injury as a complication of abdominal colorectal surgery. METHOD: All patients who underwent major colorectal abdominal surgery in our Colorectal Unit between 1996 and 2009 were analyzed. Data on nerve injury were prospectively collected. RESULTS: There were 2304 patients, of whom eight (0.3%) experienced intraoperative peripheral nerve injury. This occurred in 5/2211 (0.2%) open procedures and in 3/93 (3%) laparoscopic procedures. There was no association between intraoperative peripheral nerve injury and age, gender, body mass index, surgeon, operation time, American Society of Anesthesiology (ASA) score and urgent surgery. The use of Allen-type stirrups and a vacuum bag (in laparoscopic surgery) seemed to be protective for nerve injury in the lower and upper limbs respectively. CONCLUSION: Adequate positioning and the use of pressure-free positioning devices may prevent intraoperative peripheral nerve injury, particularly during laparoscopy.