Open Access Dissertation
Date of Award
Post-operative adhesion development occurs in the vast majority of patients following abdominal surgery and is a natural occurrence of peritoneal-wound healing. These fibrous bands may form within the first 5-7 days post-surgery and have the ability to cause a distortion in the normal anatomical positioning of abdominal organs. Consequently, adhesions are major contributors to small bowel obstruction, infertility, and severe pelvic and abdominal pain. Physiological processes responsible for adhesion formation remain obscure though it is believed to involve cell migration, proliferation, and differentiation of several cell types including mesothelial cells, fibroblasts, and inflammatory and immune cells. Substances released from these cells regulate fibrinolytic activity, tissue remodeling, angiogenesis, and extracellular matrix turnover, processes that are known to be central to the development of adhesions. Our long-term goal is to prevent or selectively limit the development of post-operative adhesions. The objective of this study is to determine the role that macrophages play in the development of post-operative adhesions. Our central hypothesis states that surgical-induced hypoxia triggers a pro-inflammatory signal, leading to the activation and recruitment of resident and infiltrating macrophages, which contribute to the development of the adhesion phenotype. This hypothesis has been formulated on the basis of strong preliminary and published data, which suggest that hypoxia plays a major role in the development of the adhesion phenotype. Indeed, we have shown that exposure of normal peritoneal fibroblasts to hypoxia, irreversibly, induces the adhesion phenotype. This phenotype is characterized by a reduction in plasminogen activator activity, increased extracellular matrix deposition, increased cytokine production, and reduced apoptosis. In this study we have shown that macrophages express basal levels of adhesion phenotype markers: TGF-beta1, VEGF, and type I collagen. Hypoxia enhances the expression of TGF-beta1, VEGF, and type I collagen through a HIF-1alpha and TGF-beta1 dependent mechanism. Additionally, macrophages exposed to hypoxia release specific factors that are responsible for inducing the adhesion phenotype in normal peritoneal fibroblasts. More specifically, hypoxia-induced TGF-beta1 expression in macrophages mediates this response through a dose-dependent mechanism. Collectively, results from this study highlight a role for the innate immune system in the pathogenesis of peritoneal wound healing and adhesion development.
White, Jennell, "The potential role of innate immunity in the pathogenesis of post-operative adhesions" (2011). Wayne State University Dissertations. 401.