Cellular and molecular regulation of fibrotic postoperative abdominal adhesions

Abdominal adhesions are fibrotic bands of tissue that form following damage to the peritoneum, affecting the majority of abdominal surgery patients and resulting in an annual clinical burden exceeding $1.7 billion. Currently, adhesiolysis (surgical removal) is the only treatment available for adhesion-related complications but reoperation comes with a high risk of morbidity and increases the likelihood of future adhesion formation, requiring novel therapeutic approaches. Although the mechanisms of adhesion formation are complex, fibroblasts play key roles in both restoration of normal tissue structure-function and pathological adhesion formation. Disruption of homeostatic wound healing pathways, perhaps through aberrant signals from immune cells or the disrupted matrix, causes fibroblasts to produce excess extracellular matrix (ECM), resulting in a tenacious, vascularized, and innervated tissue that poses an intractable risk to patient health. To achieve desirable patient outcomes, therapeutic approaches must target mechanisms that impede adhesiogenesis while facilitating wound healing. However, the identification of these mechanisms is complicated by the diverse origins of adhesion-associated fibroblasts, a poor characterization of adhesion ECM architecture, and a lack of standardized methods to model adhesiogenesis. In this review, we detail the postsurgical loss of peritoneal homeostasis and subsequent cellular response, discussing how the resulting population of adhesion-associated fibroblasts responds to cell-cell and cell-matrix communication, driving adhesion pathogenesis. Given the rapid expansion of fundamental knowledge that has been developed in the last ∼5 yr, this is a critical inflection point for the field that lays the groundwork for the identification of novel antifibrotic abdominal adhesion therapeutics.