Role of alpha-macroglobulin-elastase complexes in the pathogenesis of elastase-induced emphysema in hamsters.
Role of alpha-macroglobulin-elastase complexes in the pathogenesis of elastase-induced emphysema in hamsters.
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α-巨球蛋白-弹性蛋白酶复合物在弹性蛋白酶诱导的仓鼠肺气肿发病机制中的作用。
DOI：
10.1172/jci110531
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发表时间：
1982
期刊：
影响因子：
--
通讯作者：
Franzblau,C
中科院分区：
文献类型：
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作者：
Stone,PJ;Calore,JD;Snider,GL;Franzblau,C
将放射性标记的、酶活性的或氯甲基酮灭活的猪胰腺弹性蛋白酶经气管内注入仓鼠体内。对支气管肺灌洗液的凝胶过滤发现了两个主要的放射性组分：一个在78万道尔顿洗脱，对应于α-巨球蛋白-胰腺弹性酶复合体，另一个在68000道尔顿，对应于α-1-蛋白酶抑制物-胰腺弹性酶复合体。注入弹性酶后4d，支气管肺灌洗液中弹性蛋白溶解活性恢复，并与α-巨球蛋白-胰腺弹性酶复合体有关。这种复合体在滴注14d后即可恢复。当不到通常剂量的1%(1.5-1.7微克)的弹性蛋白酶注入金黄地鼠体内时，主要的放射性复合体是α-1-蛋白酶抑制剂-胰腺弹性酶复合体，灌洗液中很少或根本没有弹性溶解活性。与220微克弹性蛋白酶的滴注相比，这种低剂量没有检测到疾病或出血反应，并且没有出血，仅从肺中回收了少量的α-巨球蛋白-胰腺弹性酶复合体。为了研究循环中的抗蛋白酶与弹性蛋白酶的相互作用，允许仓鼠血浆直接与放射性标记的弹性蛋白酶相互作用；α-巨球蛋白比α-1-蛋白酶抑制剂结合更多的弹性酶，证实了在肺灌洗实验中的发现。仓鼠对胰腺弹性蛋白酶诱导的肺气肿的易感性可能依赖于弹性酶与保护弹性溶解潜能的α-巨球蛋白的优先结合，而不是与使弹性酶失活的α-1-蛋白酶抑制剂的优先结合。我们推测，如果在注入弹性酶后144天，在仓鼠肺中发现的残留放射性中的一小部分是具有酶活性的α-巨球蛋白-胰腺弹性酶复合体，这可能是持续弹性溶解活性的来源，这可能解释了肺损伤的进行性。
Radiolabeled, enzymatically active or chloromethyl ketone-inactivated porcine pancreatic elastase was endotracheally instilled into hamsters. Gel filtration of the bronchopulmonary lavage fluid revealed two major radioactive fractions: one, eluting at 780,000 daltons, corresponding to an alpha-macroglobulin-pancreatic elastase complex, and another, at 68,000 daltons, corresponding to an alpha-1-protease inhibitor-pancreatic elastase complex. Elastolytic activity was recovered in the bronchopulmonary lavage fluid up to 4 d after elastase instillation and was associated with the alpha-macroglobulin-pancreatic elastase complex. Small amounts of this complex were recovered 14 d after instillation. When less than 1% (1.5--1.7 micrograms) of the usual dose of elastase was instilled into hamsters, the major radioactive complex was alpha-1-protease inhibitor-pancreatic elastase complex, and little or no elastolytic activity was found in the lavage fluid. In contrast to the instillation of 220 micrograms of elastase, no disease or hemorrhagic reaction was detected with this low dose, and without hemorrhage only insignificant amounts of alpha-macroglobulin-pancreatic elastase complexes were recovered from the lungs. To study the interaction of circulating antiproteases with elastase, hamster plasma was allowed to interact directly with the radiolabeled elastase; alpha-macroglobulin bound much more of the elastase than alpha-1-protease inhibitor, confirming the findings in the lung lavage experiments. The hamster's susceptibility to pancreatic elastase-induced emphysema may depend on the preferential binding of elastase to alpha-macroglobulin, which protects the elastolytic potential, rather than to alpha-1-protease inhibitor, which inactivates elastase. We speculate that if even a fraction of the residual radioactivity found in the hamster lungs as long as 144 d after instillation of elastase represents enzymatically active alpha-macroglobulin-pancreatic elastase complex, this could serve as a source of persistent elastolytic activity, which might explain the progressive nature of the pulmonary lesion.