On Microvascular Inflammation and Intestinal Leakage in Radiation Enteropathy

Abstract: Gastrointestinal tract damage is an insidious feature in patients undergoing radiotherapy. Microvascular inflammation, including leukocyte and platelet recruitment as well as epithelial barrier dysfunction, are considered to constitute key components in the pathophysiology of radiation-induced enteropathy. The aim of this thesis was to investigate the basic mechanisms behind leukocyte-platelet-endothelial cell interactions in the colonic microcirculation and intestinal leakage in response to radiotherapy. It was found that immunoneutralization of P-selectin (CD62P) and P-selectin glycoprotein ligand-1 (CD162) abolished radiation-provoked leukocyte and platelet rolling in the colon. Moreover, inhibition of P-selectin and P-selectin glycoprotein ligand-1 also markedly decreased firm adhesion of leukocyte and platelets, suggesting that a rolling adhesive interaction is a prerequisite for subsequent leukocyte and platelet accumulation in response to radiation. However, inhibition of leukocyte and platelet recruitment or systemic depletion of leukocytes and platelets had no impact on radiation-induced intestinal leakage, suggesting that microvascular inflammation does not cause intestinal barrier dysfunction in radiation enteropathy. The role of p38 mitogen-activated protein kinase and Rho-kinase signalling was next examined by use of specific antagonists. Blocking p38 mitogen-activated protein kinase and Rho-kinase activity markedly decreased radiation-induced leukocyte and platelet recruitment in the colonic microvasculature as well as maintained intestinal integrity in response to radiotherapy. Taken together, this thesis elucidates detailed mechanisms regulating microvascular inflammation and intestinal dysfunction in radiation enteropathy. Thus, these findings not only increase our understanding of pathological tissue changes in response to radiotherapy but may also help to develop more effective and specific protective strategies for patients undergoing radiotherapy.