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Copyright ©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jun 14, 2007; 13(22): 3047-3055
Published online Jun 14, 2007. doi: 10.3748/wjg.v13.i22.3047
Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy
Junru Wang, Marjan Boerma, Qiang Fu, Martin Hauer-Jensen
Junru Wang, Department of Surgery, University of Arkansas for Medical Sciences, United States
Marjan Boerma, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, United States
Qiang Fu, Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, United States
Martin Hauer-Jensen, Department of Surgery, University of Arkansas for Medical Sciences, Surgical Service, Central Arkansas Veterans Healthcare System4, Little Rock, AR, United States
Author contributions: All authors contributed equally to the work.
Supported by National Institutes of Health, Grant CA83719 and US Department of Veterans Affairs
Correspondence to: Martin Hauer-Jensen, MD, PhD, Arkansas Cancer Research Center, 4301 West Markham, Slot 725, Little Rock, AR 72205, United States. mhjensen@life.uams.edu
Telephone: +1-501-6867912 Fax: +1-501-4210022
Received: December 15, 2006
Revised: February 3, 2007
Accepted: February 25, 2007
Published online: June 14, 2007
Abstract

This review summarizes the current state of knowledge regarding the role of endothelial dysfunction in the pathogenesis of early and delayed intestinal radiation toxicity and discusses various endothelial-oriented interventions aimed at reducing the risk of radiation enteropathy. Studies published in the biomedical literature during the past four decades and cited in PubMed, as well as clinical and laboratory data from our own research program are reviewed. The risk of injury to normal tissues limits the cancer cure rates that can be achieved with radiation therapy. During treatment of abdominal and pelvic tumors, the intestine is frequently a major dose-limiting factor. Microvascular injury is a prominent feature of both early (inflammatory), as well as delayed (fibroproliferative) radiation injuries in the intestine and in many other normal tissues. Evidence from our and other laboratories suggests that endothelial dysfunction, notably a deficiency of endothelial thrombomodulin, plays a key role in the pathogenesis of these radiation responses. Deficient levels of thrombomodulin cause loss of vascular thromboresistance, excessive activation of cellular thrombin receptors by thrombin, and insufficient activation of protein C, a plasma protein with anticoagulant, anti-inflammatory, and cytoprotective properties. These changes are presumed to be critically involved in many aspects of early intestinal radiation toxicity and may sustain the fibroproliferative processes that lead to delayed intestinal dysfunction, fibrosis, and clinical complications. In conclusion, injury of vascular endothelium is important in the pathogenesis of the intestinal radiation response. Endothelial-oriented interventions are appealing strategies to prevent or treat normal tissue toxicity associated with radiation treatment of cancer.

Keywords: Endothelial cells; Thrombomodulin; Pro-teinase-activated receptors; Radiation injuries; Radiation enteropathy