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 int...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 close-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.展开更多
This study evaluated the mechanisms of 5-fluorouracil (5-FU) induced intestinal damage by investi-gating the lipid peroxide (LPO) level, myeloperoxidase (MPO) activity and disaccharidase activity in rats.Group Ⅰ anim...This study evaluated the mechanisms of 5-fluorouracil (5-FU) induced intestinal damage by investi-gating the lipid peroxide (LPO) level, myeloperoxidase (MPO) activity and disaccharidase activity in rats.Group Ⅰ animals (n=6) were sacrificed and served as a normal control group. Group Ⅱ animaIes (n= 24 )were given a single intraperitoneal injection of 5-FU (150 mg/kg) and every 8 rats were sacrificed on day1,3 and 5 after injection respectively. Results: LPO concentration in blood and intestinal mucosa was sig-nificantly higher in the group Ⅱ than in the group Ⅰ on day 1 and 3 (P<0. 05) MPO activity was signif-icantly higher in the group I than in the group Ⅰ at different times (P<0. 01 ). Lactase activity on day 5(P<0. 01); sucrase activity (P<0. 01 and P<0. 05 respectiviely) and maltase activity (P<0. 01 ) on day3 and 5, were significantly lower in the group than in the group l. Conclusion: The results indicatethat neutrophil infiltration may be involved in 5-FU-induced lipid peroxidative damage of the small intes-tine which was reflected by the decreased disaccharidases activities.展开更多
基金National Institutes of Health, Grant CA83719US Department of Veterans Affairs
文摘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 close-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.
文摘This study evaluated the mechanisms of 5-fluorouracil (5-FU) induced intestinal damage by investi-gating the lipid peroxide (LPO) level, myeloperoxidase (MPO) activity and disaccharidase activity in rats.Group Ⅰ animals (n=6) were sacrificed and served as a normal control group. Group Ⅱ animaIes (n= 24 )were given a single intraperitoneal injection of 5-FU (150 mg/kg) and every 8 rats were sacrificed on day1,3 and 5 after injection respectively. Results: LPO concentration in blood and intestinal mucosa was sig-nificantly higher in the group Ⅱ than in the group Ⅰ on day 1 and 3 (P<0. 05) MPO activity was signif-icantly higher in the group I than in the group Ⅰ at different times (P<0. 01 ). Lactase activity on day 5(P<0. 01); sucrase activity (P<0. 01 and P<0. 05 respectiviely) and maltase activity (P<0. 01 ) on day3 and 5, were significantly lower in the group than in the group l. Conclusion: The results indicatethat neutrophil infiltration may be involved in 5-FU-induced lipid peroxidative damage of the small intes-tine which was reflected by the decreased disaccharidases activities.
