Impaired collagen synthesis in the rectum may be a molecular target in anastomotic leakage prophylaxis

Abstract

The underlying molecular mechanisms for anastomotic leakage (AL) after colorectal surgery are unknown and there are no therapeutics for AL prevention. Our aim was to correlate endogenous matrix metalloproteinase (MMP) activity, collagen concentration, and collagen/MMP/cytokine mRNA levels with anatomic location in human colorectal tissue. We enrolled 22 patients in this prospective study: 7 underwent elective laparoscopic sigmoid resection and 15 underwent low anterior resection for colorectal cancer. Full-thickness intestinal tissue rings from anastomoses constructed with a circular stapler were used for the determination of the MMP activity, tissue collagen concentration and mRNA levels. COL1A1 (p = 0.017) and COL3A1 (p = 0.0013) mRNA levels were lower in rectal tissue than in colonic samples. Neither MMP activities nor collagen concentrations differed significantly between the two anatomic locations. By elucidating the factors responsible for the decreased collagen production we may identify specific molecular targets in AL prophylaxis.

A Human Cellular Model for Colorectal Anastomotic Repair: The Effect of Localization and Transforming Growth Factor-β1 Treatment on Collagen Deposition and Biomarkers

“…The accumulated collagen was the main outcome in this study. No significant differences in the capacity to form insoluble collagen by fibroblasts isolated from the rectum or colon were found, which corroborates earlier in vivo measurements [35]. This conclusion is based on the evaluation of 38 different fibroblast strains from 19 colorectal patients.…”

“…This conclusion is based on the evaluation of 38 different fibroblast strains from 19 colorectal patients. On the other hand, the observed reduction in mRNA levels of COL1A1 and COL3A1, as indicators of reduced type I collagen and type III collagen synthesis in the rectum versus colon, were not translated into fibroblasts in the present study [35]. One possible explanation is that mRNA levels in vivo reflect quiescent conditions whereas culturing activates fibroblasts including their collagen synthesis machinery similar to a wound healing situation.…”

“…Patients older than 18 years with colorectal cancer who underwent elective laparoscopic sigmoid resection (SR) or low anterior resection (LAR) with primary anastomosis using a circular stapler were invited to participate [35]. Patients subjected to emergency operation, inflammatory bowel disease, active diverticulitis, ileorectal or ileocolic anastomosis, or interpreter care were excluded.…”

“…We recently demonstrated decreased COL1A1 and COL3A1 mRNA levels in the rectum compared to colon, which may explain the higher risk of AL after rectal resection compared to colonic resection [35]. The primary aim of this study (DONUT2) was to (1) compare collagen production using fibroblasts isolated from the colon and rectum and (2) determine the effect of TGF-β1 on isolated fibroblasts.…”

Glucagon-Like Peptide-2 Analogue ZP1849 Augments Colonic Anastomotic Wound Healing

“…The predominant collagen subtypes in colorectal tissue are type I and type III. Recently, we showed a decreased collagen synthesis capacity, measured as type I procollagen (COL1A1) and type III procollagen (COL3A1) mRNA levels, the more distal the anastomosis in colorectal patients [ 6 ]. This alteration in the collagen synthesis capacity is then a possible explanation for the higher incidence of AL the lower the anastomosis.…”