Abstract
Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.
Highlights
Radiation therapy is an important part of cancer treatment, with approximately 50% of all cancer patients receiving radiation therapy during treatment, it induces acute and chronic inflammation in healthy organs [1]
Radiation proctitis decreases the quality of life of patients receiving radiation therapy, who often require either interruption of therapy or other modifications that may forestall the optimal completion of the original treatment plan
Activation of TM by pravastatin resulted in the recovery of endothelial dysfunction and decreased inflammatory response. These results suggested that pravastatin can protect from radiation proctitis by upregulating TM expression in endothelial cells, thereby attenuating inflammatory response and improving epithelial damage
Summary
Radiation therapy is an important part of cancer treatment, with approximately 50% of all cancer patients receiving radiation therapy during treatment, it induces acute and chronic inflammation in healthy organs [1]. Patients is associated with hemorrhage, with stenosis occurring in approximately 1% and fistula formation in 0.4% patients [4,5,7]. Histopathological changes, such as damage throughout the gut well, vascular dystrophy, and uncontrolled scarring leading to tissue fibrosis have been observed [4,8]. Radiation proctitis decreases the quality of life of patients receiving radiation therapy, who often require either interruption of therapy or other modifications that may forestall the optimal completion of the original treatment plan
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