Modelling therapies for surgical adhesions

In this project we will discover new medical treatments to prevent the formation of internal scars, or 'adhesions'.

People often have to undergo operations which involve opening up their abdomens e.g. to cut out a tumour or an inflamed appendix. A common complication after these operations is the development of adhesions which can glue our guts together. These adhesions are painful and can even cause guts to become blocked and stop working. This then requires a major operation to put things right, yet these second operations may themselves lead to more adhesions.

We will work out how cells inside the abdomen form scars after operations and then use this knowledge to block the process. We will also work out ways to grow scars outside of the body. This will make it easier for us to monitor how well our new therapies are working.

By the end of the project, we aim to have a list of new medicines which can then be tested to help people who suffer from recurrent adhesions.

Surgical adhesions can cause severe and chronic abdominal pain and life-threatening intestinal obstruction. Although they constitute an enormous socioeconomic burden, there are no effective preventative strategies. Reduced lysis of a post-surgical fibrin-rich clot is an important trigger in the initiation of adhesion development. Critically, a lack of understanding of the aberrant molecular and cellular mechanisms driving mature adhesion formation beyond this first step precludes the rational design of novel biological therapies.

Therefore, we will address the following related hypotheses. 1. Aberrant biological signalling pathways mediate key steps in adhesion formation. 2. Peritoneal mesothelial cells contribute to adhesions via epithelial-mesenchymal transition and 3. Inhibiting these key aberrant biological events will prevent adhesion formation.

We will combine surgical and transgenic strategies in mice with human culture models to successfully address these questions. First, we will replicate the human clinical scenario in a robust mouse model of surgical adhesion formation. Using Wt1CreERT2;Rosa26mTmG mice will allow us, for the first time, to lineage trace mesothelial cells during adhesion formation. We will define aberrant signalling pathways using biochemical techniques, and localise them to cell populations within the forming scar by immunohistology. Consequently, we will use specific reagents to block adhesion formation in the same in vivo model.

In parallel, we will establish monolayer and 3D human cell culture models in which mesothelial cells are triggered to form an adhesion by adding fibrin clot. With these systems, we will establish whether the same biological therapies tested in mice can block human adhesion formation ex vivo.

Our experimental strategy will not only illuminate the pathobiology of adhesion formation, but also pave the way for Phase 1 trials of novel biological therapies to prevent adhesions forming in humans.

Scientific research impact. The basic science behind surgical adhesion formation has been a neglected research field, especially bearing in mind the scale of human morbidity and economic burden associated with the condition. Excitingly, however, links between tissue repair and fibrosis, and their relation to normal embryonic development and cancer progression, are increasingly appreciated. In particular, the ability of epithelial cells to change phenotype and become myofibroblasts through a process of epithelial-mesenchymal transition. Our project is timely and combines the clinical discipline of surgery with the basic sciences of mouse genetics and cell/molecular biology. Due to its broad scope, the results will be of direct relevance to the clinical and science research communities, including general surgeons, gynaecologists, and cell and developmental biologists.

Novel technology and translational impact. One aim is to generate a novel human 3D peritoneal call assay system which would have a huge impact on the academic and commercial community. The use of pure well characterised populations of primary human mesothelial cells derived by brushing the peritoneal surface (similar to bronchial brushings for airway epithelial cells) will be a first and banking these cells so they are available to the wider scientific community will be of immense and immediate value. In addition, a physiologically relevant in vitro model of the peritoneum that may be used in combination with diseased cells will be of great interest to a number of stakeholders as it will reduce and replace the requirement for animal studies (3Rs) in particular in the fields of tumour metastasis, peritonitis and endometriosis. Furthermore, the safety assessment committee urgently requires more human based research models to assure safety of their new compounds and so this model would be of great significance.

Societal and health impact. Surgical adhesions and their associated complications such as severe chronic pain, bowel obstruction and infertility in women, represent a huge health problem world-wide. Surgery is the only way to detect and treat already-formed adhesions but surgery itself also causes adhesions. The cost of adhesion-related complications for the NHS are an estimated £67 million each year. At present there are no pharmacological ways of preventing adhesion formation, and current physical therapies (e.g. degradable membranes and gel barriers) show limited efficacy. Any advance in developing efficient anti-adhesion agents would have enormous consequences for the range of surgical specialities. Furthermore, because surgical adhesions are associated or resemble other pathologies such as encapsulating peritoneal sclerosis, endometriosis, and cancer-, radiation-, infection- as well as dialysis-induced peritoneal sclerosis, the results of our project could potentially have widespread benefits in a number of clinically important areas.