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金属蛋白酶抑制可预防实验性急性肺血栓栓塞症中心肌细胞损伤。

Metalloproteinase inhibition protects against cardiomyocyte injury during experimental acute pulmonary thromboembolism.

机构信息

Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.

出版信息

Crit Care Med. 2011 Feb;39(2):349-56. doi: 10.1097/CCM.0b013e3181fa3dfe.

DOI:10.1097/CCM.0b013e3181fa3dfe
PMID:20890187
Abstract

OBJECTIVES

Up-regulated matrix metalloproteinases may be involved in the development of cardiomyocyte injury and the degradation of troponin associated with acute pulmonary thromboembolism. We examined whether pretreatment with doxycycline (a nonspecific matrix metalloproteinase inhibitor) protects against cardiomyocyte injury associated with acute pulmonary thromboembolism.

DESIGN

Controlled animal study.

SETTING

University research laboratory.

SUBJECTS

Mongrel dogs.

INTERVENTIONS

Anesthetized animals received doxycycline (10 mg/kg intravenously) or saline and acute pulmonary thromboembolism was induced with autologous blood clots injected into the right atrium. Control animals received doxycycline (or saline).

MEASUREMENTS AND MAIN RESULTS

Hemodynamic measurements were performed, and acute pulmonary thromboembolism increased baseline mean pulmonary arterial pressure and pulmonary vascular resistance by approximately 160% and 362%, respectively (both p < .05), 120 mins after acute pulmonary thromboembolism. Pretreatment with doxycycline attenuated these increases (to 125% and 232%, respectively; both p < .05). Although acute pulmonary thromboembolism tended to increase the right ventricle maximum rate of isovolumic pressure development and the maximum rate of isovolumic pressure decay, doxycycline produced no effects on these parameters. Gelatin zymograms of right ventricle showed that acute pulmonary thromboembolism marginally increased matrix metalloproteinase-9 (but not matrix metalloproteinase-2) levels in the right ventricle. A fluorometric assay to assess net matrix metalloproteinase activities showed that acute pulmonary thromboembolism increased matrix metalloproteinase activities in the right ventricle by >100% (p < .05), and this finding was confirmed by in situ zymography of the right ventricle. Doxycycline attenuated acute pulmonary thromboembolism-induced increases in right ventricle matrix metalloproteinase activities. Acute pulmonary thromboembolism induced neutrophil accumulation in the right ventricle, as estimated by myeloperoxidase activity, and doxycycline blunted this effect (p < .05). Serum cardiac troponin I concentrations, which reflect cardiomyocyte injury, increased after acute pulmonary thromboembolism, and this increase was attenuated by pretreatment with doxycycline (p < .05).

CONCLUSIONS

We found evidence supporting the idea that acute pulmonary thromboembolism is associated with increased matrix metalloproteinase activities in the right ventricle, which may lead to degradation of sarcomeric proteins, including cardiac troponin I. Inhibition of matrix metalloproteinases may be an effective therapeutic intervention in the management of acute pulmonary thromboembolism.

摘要

目的

细胞外基质金属蛋白酶的上调可能与急性肺血栓栓塞症相关的心肌细胞损伤和肌钙蛋白降解有关。我们研究了预先给予强力霉素(一种非特异性基质金属蛋白酶抑制剂)是否能预防与急性肺血栓栓塞症相关的心肌细胞损伤。

设计

对照动物研究。

地点

大学研究实验室。

实验对象

杂种狗。

干预措施

麻醉动物接受强力霉素(10mg/kg 静脉内)或生理盐水,并通过将自体血凝块注入右心房来诱导急性肺血栓栓塞症。对照动物接受强力霉素(或生理盐水)。

测量和主要结果

进行血流动力学测量,急性肺血栓栓塞症使基础平均肺动脉压增加约 160%,肺血管阻力增加约 362%(均 p<.05),在急性肺血栓栓塞症后 120 分钟。预先给予强力霉素可减弱这些增加(分别为 125%和 232%;均 p<.05)。尽管急性肺血栓栓塞症趋向于增加右心室最大等容压力发展速率和最大等容压力衰减速率,但强力霉素对这些参数没有影响。右心室明胶酶谱显示,急性肺血栓栓塞症使右心室基质金属蛋白酶-9(但不是基质金属蛋白酶-2)水平略有增加。荧光法评估净基质金属蛋白酶活性表明,急性肺血栓栓塞症使右心室基质金属蛋白酶活性增加了>100%(p<.05),并且这一发现通过右心室原位酶谱得到了证实。强力霉素减弱了急性肺血栓栓塞症引起的右心室基质金属蛋白酶活性增加。急性肺血栓栓塞症引起右心室中性粒细胞积聚,用髓过氧化物酶活性估计,强力霉素减弱了这一作用(p<.05)。血清心肌肌钙蛋白 I 浓度反映了心肌细胞损伤,在急性肺血栓栓塞症后增加,强力霉素预处理可减弱这种增加(p<.05)。

结论

我们发现了支持急性肺血栓栓塞症与右心室基质金属蛋白酶活性增加相关的证据,这可能导致包括心肌肌钙蛋白 I 在内的肌节蛋白的降解。基质金属蛋白酶的抑制可能是急性肺血栓栓塞症治疗的有效干预措施。

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