Modulation of S100a4 in post-operative abdominal adhesion complications

Abstract Abdominal adhesions are the leading cause of small bowel obstructions, and result when scar tissue forms between the abdominal wall and visceral organs, such as the small intestine, in response to peritoneal tissue trauma during abdominal and pelvic surgery. Adhesion formation occurs in greater than 50% of cases, with the incidence rising to >95% in patients undergoing multiple surgeries. In addition to small bowel obstructions, adhesions can also lead to infertility and chronic pain, and can complicate subsequent surgeries. Collectively, health care costs associated with abdominal adhesion-related complications exceed $5 billion annually in the United States. Currently, standard treatment options for abdominal adhesions are limited to laparoscopic or open surgical lysis. Thus, there is a substantial need to identify therapies to both prevent initial adhesion formation and to ameliorate adhesion persistence and recurrence. However, the mechanisms that drive post- operative adhesion formation are only partially defined, leading to a paucity of translationally relevant therapies. Our exciting preliminary demonstrate that genetic knockdown of the small calcium binding protein, S100a4 results in significant attenuation of adhesion formation. Therefore, in Aim 1 we will leverage this anti- fibrotic mouse model to comprehensively define the temporal molecular programs underpinning adhesion formation and resistance to adhesions. Our preliminary data demonstrates that S100a4 is expressed by both macrophages and fibroblasts/myofibroblasts during adhesion pathogenesis, while S100a4 can function through direct cell-intrinsic functions or as a secreted signaling molecule. Therefore, in Aim 2, we will delineate cell-type specific requirements for S100a4 in adhesion formation and subsequent small bowel obstruction using conditional knockout models and establish the mechanistic functions of S100a4 using pharmacological inhibition and neutralizing antibody approaches. Finally, our preliminary data suggest that delayed, short-term treatment with an S100a4 inhibitor is sufficient to ameliorate mature adhesions. Therefore, in Aim 3, we will leverage this approach to define the mechanisms of adhesion resolution and determine whether short-term S100a4 is sufficient to prevent adhesion recurrence. Collectively, these studies will provide critical insights into the fundamental mechanisms of adhesion formation and amelioration, define the mechanisms through which S100a4 drives adhesion formation, and establish the translational potential of S100a4 inhibition as means to prevent or resolve post-operative abdominal adhesions and adhesion-related small bowel obstructions.