Hypothesis: Role for the circadian Clock system and sleep in the pathogenesis of adhesions and chronic pelvic pain?

Abstract

Intra-peritoneal adhesions ensuing from surgery or infection may lead to chronic pelvic pain, bowel obstruction, infertility and additional invasive surgery to resolve adhesion-related complications. As a result adhesions are a major clinical, social and economic concern. The cumulative year-on-year direct costs of adhesion-related readmissions for a 10-year period are more than £ 569 million. The degree of intra-abdominal adhesion formation in an individual patient after a surgical or infective insult remains difficult to predict. This reflects a lack of understanding as to the underlying aetiologies. Several different mechanisms leading to adhesion formation and re-formation have been proposed. These include abnormal modulations in inflammatory status, fibrinolytic pathways and matrix remodelling. A number of preventative strategies have been designed accordingly. However, although each individual model offers specific insights into the aetiology of adhesion formation, none have been shown to provide the basis for a highly effective clinical intervention. A unifying fundamental mechanism remains elusive. In this article we propose that such a mechanism can be found within the molecular control of circadian rhythms and "Clock" gene biology. A number of physiological processes demonstrating circadian variation have been shown to involve 'Clock genes' in the suprachiasmatic nucleus (SCN), which then entrains a similar set of Clock genes in peripheral tissues such as the heart, brain, spleen, lung, liver, skeletal muscle and kidney. The intrinsic time-keeping system influences activity, such as sleep, temperature regulation, rates of metabolism, immune responses, blood pressure and hormone secretion. The function and availability of mediators involved in the inflammatory response, fibrinolytic and anti-coagulation pathways are all under the tight control of the molecular Clock system. These include IL-6, PAI-1, fibrinogen, fibroblasts and TNF-α. We hypothesise that disruptions in the 'Clock system' are central to the causal pathway of adhesion formation. Our hypothesis takes into consideration and utilises current understanding in the field uniting individual principles. Moreover; this hypothesis suggests strategies for optimising existing therapeutic interventions.