Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy

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.

Figure 1

Model of interaction between epithelial and endothelial radiation injury in the intestine demonstrating how endothelial dysfunction may exacerbate the early intestinal radiation response and “drive” the cycle of chronicity of intestinal radiation fibrosis. Radiation causes epithelial crypt cell death, leading to insufficient replacement of the villus epithelium, and breakdown of the epithelial barrier that normally separates intestinal tissue from the intraluminal contents of the intestine. Simultaneously, radiation causes endothelial dysfunction, notably loss of thromboresistance and increased expression of chemokines and adhesion molecules. The combination of loss of epithelial barrier function and endothelial dysfunction enhances the post-radiation inflammatory response, inhibits restitution of the epithelium, and promotes extracellular matrix deposition.

Figure 2

The coagulation cascade. Simplified diagram of the coagulation “cascade” with the intrinsic, extrinsic, and common pathways. Note how thrombomodulin, located on the luminal surface of endothelial cells, forms a complex with thrombin, which is converted from a pro-coagulant to an anticoagulant and how activated protein C (APC) limits thrombin generation by feed-back into the intrinsic and common coagulation pathways. See text for further details.

Figure 3

Proposed model linking radiation-induced endothelial dysfunction to chronic inflammation and progressive intestinal fibrosis via chronic PAR₁ activation. Radiation causes TM deficiency in endothelial cells, leading to insufficient “scavenging” of locally formed thrombin. Thrombin exerts pro-coagulant, pro-inflammatory, mitogenic, and pro-fibrogenic effects on mesenchymal cells (smooth muscle cells, fibroblasts, and myofibroblasts), as well as other cell types in the irradiated tissue. Feed-back by cytokines and other inflammatory mediators sustains the endothelial TM deficiency and thus contributes to the chronicity of radiation injury.