RGD Reference Report - Deficiency of microvascular thrombomodulin and up-regulation of protease-activated receptor-1 in irradiated rat intestine: possible link between endothelial dysfunction and chronic radiation fibrosis. - Rat Genome Database

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Deficiency of microvascular thrombomodulin and up-regulation of protease-activated receptor-1 in irradiated rat intestine: possible link between endothelial dysfunction and chronic radiation fibrosis.

Authors: Wang, J  Zheng, H  Ou, X  Fink, LM  Hauer-Jensen, M 
Citation: Wang J, etal., Am J Pathol 2002 Jun;160(6):2063-72.
RGD ID: 634507
Pubmed: PMID:12057911   (View Abstract at PubMed)
PMCID: PMC1850827   (View Article at PubMed Central)
DOI: DOI:10.1016/S0002-9440(10)61156-X   (Journal Full-text)

Microvascular injury is believed to be mechanistically involved in radiation fibrosis, but direct molecular links between endothelial dysfunction and radiation fibrosis have not been established in vivo. We examined radiation-induced changes in endothelial thrombomodulin (TM) and protease-activated receptor-1 (PAR-1) in irradiated intestine, and their relationship to structural, cellular, and molecular aspects of radiation injury. Rat small intestine was locally exposed to fractionated X-radiation. Structural injury was assessed 24 hours and 2, 6, and 26 weeks after the last radiation fraction using quantitative histology and morphometry. TM, neutrophils, transforming growth factor-beta, and collagens I and III were assessed by quantitative immunohistochemistry. PAR-1 protein was localized immunohistochemically, and cells expressing TM or PAR-1 transcript were identified by in situ hybridization. Steady-state PAR-1 mRNA levels in intestinal smooth muscle were determined using laser capture microdissection and competitive reverse transcriptase-polymerase chain reaction. Radiation caused a sustained, dose-dependent decrease in microvascular TM. The number of TM-positive vessels correlated with all parameters of radiation enteropathy and, after adjusting for radiation dose and observation time in a statistical model, remained independently associated with neutrophil infiltration, intestinal wall thickening, and collagen I accumulation. PAR-1 immunoreactivity and transcript increased in vascular and intestinal smooth muscle cells in irradiated intestine. PAR-1 mRNA increased twofold in irradiated intestinal smooth muscle. Intestinal irradiation up-regulates PAR-1 and causes a dose-dependent, sustained deficiency of microvascular TM that is independently associated with the severity of radiation toxicity. Interventions aimed at preserving or restoring endothelial TM or blocking PAR-1 should be explored as strategies to increase the therapeutic ratio in clinical radiation therapy.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to X-ray  IEP 634507 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Thbd  (thrombomodulin)

Objects referenced in this article
Gene F2r coagulation factor II (thrombin) receptor Rattus norvegicus

Additional Information