Radiation injury and the protein C pathway.
OBJECTIVE
To summarize current knowledge regarding the role of the thrombomodulin (TM)-protein C system in acute and chronic radiation responses in normal tissues.


METHODS
Studies published in the biomedical literature during the past three decades and cited in PubMed and unpublished clinical and laboratory data from our own research program. STUDY SUMMARY: The risk of injury to normal tissues limits the cancer cure rates that can be achieved with radiation therapy. Microvascular injury is a prominent feature of normal tissue radiation injury and plays a critical role in both acute (inflammatory) and chronic (fibrotic) radiation responses. Evidence from our own and other laboratories strongly suggests that dysfunction of the TM-protein C system plays a key role in the pathogenesis of radiation-induced injury to normal tissue. Exposure of normal tissues to ionizing radiation causes a pronounced, sustained deficiency of endothelial TM. This is likely to be due to a combination of initial inactivation of TM by reactive oxygen species, reduced transcription of TM, and release of TM into the circulation. Deficient levels of endothelial TM cause loss of local vascular thrombo-resistance, excessive activation of protease-activated receptor-1 by thrombin, and insufficient activation of protein C. These changes are presumed to be critically involved in many aspects of acute radiation toxicity and in sustaining the fibroproliferative processes that lead to chronic radiation-induced organ dysfunction and clinical complications.


CONCLUSIONS
Injury of vascular endothelium may be key to the acute responses of normal tissues to ionizing radiation and to the progressive nature of chronic radiation fibrosis. Restitution of the TM-protein C pathway is an appealing strategy by which to prevent or treat normal tissue toxicity associated with radiation treatment of cancer.
Hauer-Jensen
Martin
M
Department of Surgery and Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA. mhjensen@life.uams.edu
Fink
Louis M
LM
Wang
Junru
J
D004727:Endothelium / Q000528:radiation effects; D006801:Humans; D007422:Intestines / Q000528:radiation effects; D009369:Neoplasms / Q000532:radiotherapy; D011486:Protein C / Q000502:physiology*; D011832:Radiation Injuries / Q000276:immunology* / Q000517:prevention & control; D018180:Thrombomodulin / Q000502:physiology
D011486:Protein C; D018180:Thrombomodulin