Short-Term Inhibition of ADP-Induced Platelet Aggregation by Clopidogrel Ameliorates Radiation-Induced Toxicity in Rat Small Intestine

Junru Wang; Christopher M. Albertson; Huaien Zheng; Louis M. Fink; Jean-Marc Herbert; Martin Hauer-Jensen

doi:10.1055/s-0037-1612954

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 87(01): 122-128
DOI: 10.1055/s-0037-1612954

Review Article

Schattauer GmbH

Short-Term Inhibition of ADP-Induced Platelet Aggregation by Clopidogrel Ameliorates Radiation-Induced Toxicity in Rat Small Intestine

Authors

Junru Wang

¹ University of Arkansas for Medical Sciences
Christopher M. Albertson

¹ University of Arkansas for Medical Sciences
Huaien Zheng

¹ University of Arkansas for Medical Sciences
Louis M. Fink

¹ University of Arkansas for Medical Sciences

² Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
Jean-Marc Herbert

³ Sanofi-Synthélabo, Toulouse, France
Martin Hauer-Jensen

¹ University of Arkansas for Medical Sciences

² Central Arkansas Veterans Healthcare System, Little Rock, AR, USA

Abstract

Summary

Endothelial dysfunction and increased platelet aggregation may be involved in the pathogenesis of normal tissue radiation toxicity. This study assessed clopidogrel, an inhibitor of ADP-induced platelet aggregation, as a modulator of intestinal radiation injury (radiation enteropathy).

Rat small intestine was exposed to 21 Gy X-radiation. Clopidogrel (20 mg/kg/day) or vehicle was administered from 2 days before to 10 days after irradiation. Structural radiation injury, neutrophil infiltration, smooth muscle cell proliferation, collagen content, and TGF-β1 expression were assessed 2 weeks (early phase) and 26 weeks (delayed phase) after irradiation, using quantitative histology and immunohistochemistry, morphometry, and real-time fluorogenic probe RT-PCR.

Irradiated intestine exhibited significant histopathologic injury, reduced mucosal surface area, vascular sclerosis, intestinal wall fibrosis, increased collagen content, and increased TGF-β1 expression. Clopidogrel reduced ADP-induced platelet aggregation by 93% and significantly attenuated the severity of post-radiation vascular sclerosis (p = 0.004 and p = 0.02) and the loss of mucosal surface area (p = 0.0008 and p = 0.003) at both 2 and 26 weeks. Clopidogrel also ameliorated overall histopathologic injury (p = 0.02), relative intestinal collagen content (p = 0.03), and collagen III immunoreactivity levels 2 weeks after irradiation, and caused a borderline reduction in the radiation-induced increase in extracellular matrix-associated TGF-β immunoreactivity at 26 weeks (p = 0.04). The effects of clopidogrel on steady-state TGF-β1 mRNA levels and neutrophil infiltration were not statistically significant.

Short-term clopidogrel administration affords protection against early and, to a lesser extent, delayed radiation enteropathy. Modulation of platelet aggregation should be subject to further studies as a potential method to increase safety and efficacy of radiation therapy.

Keywords

Platelet aggregation - clopidogrel - radiation therapy - intestines - radiation injuries - experimental

Full Text

References

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