The gap in surgical footprints : the role of connexin43 during post-surgical peritoneal adhesion formation

Abstract

Almost like a surgical footprint, post-surgical adhesions have been reported to develop in at least 93% of patients undergoing intra-abdominal operations. Their presence may spawn serious clinical issues, such as secondary infertility. By providing a conduit for intercellular communication, it is likely that connexins may play a pivotal role in the regulation and coordination of cellular events during adhesion formation. However, little is known about their contribution to adhesion formation, especially Connexin43, which is the most abundant and ubiquitous isoform in mammalian cells. In this study, the role of Connexin43 during adhesion formation was explored using ex vivo and in vivo models of adhesion formation. A novel mouse peritoneal strip ex vivo model was established and demonstrated to reproducibly generate adhesions. Through this model, regions of adhesion were observed to have higher Connexin43 protein levels, hinting the possible involvement of Connxin43 during adhesion formation. This phenomenon was further investigated in an in vivo ischaemic button model of adhesion formation. During early adhesion formation, a pathological increase of Connexin43 levels was observed in the mesothelial regions of the ischaemic button where adhesions are likely to occur in the model. The significance of this pathological increase was further pursued through the use of Connexin43 antisense oligodeoxynucleotides. Treatment with Connexin43 antisense oligodeoxynucleotides saw a reduction in adhesion strength and severity, which was corroborated by observations of reduced collagen deposition and fibroblast activation. Also, increased plasminogen-activating activity in the peritoneal cavity was noted. Further assessments of the treatment during early adhesion formation events showed that the knockdown of Connexin43 was accompanied with notable reductions in leukocyte recruitment and TGF-β1 levels. Together, these findings suggest that Connexin43 plays a pivotal role in adhesion formation, which opens up new avenues for developing connexin-based therapeutics for post-surgical peritoneal adhesions.