Short-Term Inhibition of ADP-Induced Platelet Aggregation by Clopidogrel Ameliorates Radiation-Induced Toxicity in Rat Small Intestine
Short-Term Inhibition of ADP-Induced Platelet Aggregation by Clopidogrel Ameliorates Radiation-Induced Toxicity in Rat Small Intestine
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氯吡格雷短期抑制 ADP 诱导的血小板聚集可改善大鼠小肠中辐射诱导的毒性
作者：
Junru Wang;C. Albertson;Huaien Zheng;L. Fink;J. Herbert;M. Hauer
内皮功能障碍和血小板聚集增加可能参与正常组织辐射毒性的发病机制。本研究评估了氯吡格雷（ADP诱导的血小板聚集抑制剂）作为肠道放射性损伤（放射性肠病）的调节剂。大鼠小肠暴露于21戈伊X射线。从照射前2天至照射后10天给予氯吡格雷（20 mg/kg/天）或溶媒。在照射后2周（早期）和26周（延迟期），采用定量组织学和免疫组织化学、形态计量学和实时荧光探针RT-PCR评估结构放射损伤、中性粒细胞浸润、平滑肌细胞增殖、胶原含量和TGF-β1表达。照射后肠组织病理学改变明显，黏膜表面积减少，血管硬化，肠壁纤维化，胶原含量增加，TGF-β1表达增加。氯吡格雷可使ADP诱导的血小板聚集减少93%，并在2周和26周时显著减轻放射后血管硬化的严重程度（p = 0.004和p = 0.02）和粘膜表面积的损失（p = 0.0008和p = 0.003）。氯吡格雷还改善了总体组织病理学损伤（p = 0.02）、相对肠胶原含量（p = 0.03）和照射后2周的III型胶原免疫反应性水平，并在26周时导致放射诱导的细胞外基质相关TGF-β免疫反应性增加的临界降低（p = 0.04）。氯吡格雷对稳态TGF-β1 mRNA水平和中性粒细胞浸润的影响无统计学意义。氯吡格雷短期给药可预防早期放射性肠病，并在较小程度上预防延迟性放射性肠病。调节血小板聚集是提高放射治疗安全性和有效性的一种潜在方法，值得进一步研究。
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.
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DOI：
--
发表时间：
2001
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Wang,J;Zheng,H;Hauer-Jensen,M
通讯作者：
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DOI：
10.1016/s0002-9440(10)65741-0
发表时间：
1998-11
期刊：
The American journal of pathology
影响因子：
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作者：
Junru Wang;Huaien Zheng;C. Sung;K. Richter;M. Hauer-Jensen
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影响因子：
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作者：
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影响因子：
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作者：
Law,MP
通讯作者：
Law,MP