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目的 探讨乌司他丁( UTI)对急性百草枯中毒致心肌损伤的保护作用及机制.方法 将24只健康日本大耳白兔按随机数字表法均分为对照组、模型组(腹腔注射百草枯37 mg/kg1次)及UTI低、高剂量组(染毒前1周开始分别静脉注射UTI 25 kU·kg-1·d-1、50 kU·kg-1·d-1,共9d)4组.于末次给药后24h称重并处死动物,取左心室组织,测定羟脯氨酸(HYP)含量；用逆转录-聚合酶链反应(RT-PCR)检测基质金属蛋白酶2(MMP-2)、金属蛋白酶组织抑制剂2(TIMP-2)转录水平；行免疫组化染色观察心肌形态学及MMP-2免疫组化评分.结果 与对照组相比,模型组心肌HYP含量(mg/g)明显增高(3.85±0.36比2.52±0.29,P＜0.05)；心肌组织MMP-2 mRNA表达及免疫组化评分(分)明显增高(mRNA:2.07±0.57比1.00±0.35；免疫组化评分:2.24±0.82比1.40±0.62,均P＜0.05),同时TIMP-2 mRNA表达呈下降趋势(0.78±0.24比1.00±0.17,P＞0.05)；组织形态学显示心肌排列紊乱.与模型组相比,UTI低、高剂量组心肌HYP含量降低(3.40±0.48、3.12±0.43比3.85±0.36,P＞0.05和P＜0 05)；MMP-2 mRNA表达和免疫组化评分明显降低(mRNA:1.86±0.44、1.58±0.46比2.07±0.57,P＞0.05和P＜0.05；免疫组化评分:1.93±0.86、1.75±0.67比2.24±0.82,均P＜0.05);TIMP-2 mRNA表达虽升高,但差异无统计学意义(0.82±0.35、0.94±0.33比0.78±0.24,均P＞0.05)；且心肌纤维排列紊乱程度减轻.结论 UTI具有改善急性百草枯中毒致心肌功能障碍及心肌间质纤维化的作用,这一作用可能与其下调组织MMP-2水平有关,且这种下调作用呈剂量依赖性.

Objective To investigate the effects of ulinastatin ( UTI ) on myocardial injury induced by acute paraquat poisoning.Methods Twenty-four Japan white rabbits were divided into control group,model group (37 mg/kg paraquat intraperitoneally once),UTI low dosage group and high dosage group (25 kU·kg-1·d-1 and 50 kU ·kg-1 ·d-1 UTI was intravenously injected respectively for 9 days beginning from 1 week before poisoning) through random number table.Rabbits were sacrificed 24 hours after the last UTI administration.Left ventricle of hearts were harvest,and tissue hydroxyproline (HYP) contents were determined.Matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) transcritional levels were assayed respectively with reverse transcription-polymerase chain reaction (RT-PCR).Expression levels of MMP-2 in tissue of left ventricle were quantified with immunohistochemistry.Results Compared with normal myocardium,acute paraquat poisoning induced elevated HYP (mg/g) content significantly (3.85 ±0.36 vs.2.52 ±0.29,P＜0.05); with RT-PCR and immunohistochemistry,it was shown that both mRNA expression levels and immunohistochemistry score of MMP-2 were much higher (mRNA:2.07 ±0.57 vs.1.00 ±0.35; immunohistochemistry score:2.24 ±0.82 vs.1.40 ±0.62,both P＜0.05 ).TIMP-2 appeared to be down-regulated in mRNA expression level (0.78 ± 0.24 vs.1.00 ± 0.17,P＞0.05).Disorganized cadiocytes were observed.Compared with paraquat poisoning model, low and high UTI administration produced depression of tissue HYP contents ( 3.40 ± 0.48,3.12 ± 0.43 vs.3.85 ± 0.36,P＞0.05 and P＜0.05 ).With low or high dosage of UTI reduced mRNA expression levels and immunohistochemical scores of MMP-2 in left ventricle were observed (mRNA: 1.86 ±0.44, 1.58 ±0.46 vs.2.07 ±0.57,P ＞0.05 and P ＜0.05;immunohistochemical score:1.93 ± 0.86,1.75 ± 0.67 vs.2.24 ± 0.82,both P＜0.05 ),and TIMP-2 mRNA level was increased slightly,though there was no significant differences (0.82 ± 0.35,0.94 ± 0.33 vs.0.78 ± 0.24,both P＞0.05).Improvements in disordered myocardium were demonstated.Conclusions UTI significantly attenuated myocardial injury induced by acute paraquat poisoning.Its mechanism might be related to a reduction of expression level of MMP-2 in tissue,with a dose-dependent manner.