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首页> 外文期刊>American Journal of Physiology >Novel aspects of urokinase function in the injured lung: role of alpha_2-macroglobulin
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Novel aspects of urokinase function in the injured lung: role of alpha_2-macroglobulin

机译：尿激酶功能在受伤的肺中的新方面：α_2-巨球蛋白的作用

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摘要

The level of active urokinase (uPA) is decreased in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALLAJRDS) whereas alpha_2-macroglobulin (alpha_2-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of qalpha_2-M to form complexes with uPA in vitro, we hypothesized that alpha2-M may interact with uPA in the lung to modulate its biological activity. Pulmonary edema fluids and lung tissues from patients with ALI/ARDS were evaluated for the presence of uPA associated with alpha2-M. Complexes between alpha2-M and uPA were detected in alveolar edema fluids as well as in lungs of patients with ALI/ARDS where they were located mainly in close proximity to epithelial cells. While uPA bound to alpha2-M retains its amidolytic activity towards low-molecular-weight substrates, it is not inhibited by its main physiological inhibitor, plasminogen activator inhibitor 1. We also investigated the functional consequences of formation of complexes between uPA and alpha2-M in vitro. We found that when alpha2-M:uPA complexes were added to cultures of human bronchial epithelial cells (BEAS-2B), activation of nuclear factor-kB as well as production of interleukin-6 and -8 was substantially suppressed compared with the addition of uPA alone. Our findings indicate for the first time that the function of uPA in patients with ALI/ARDS may be modulated by alpha2-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA.
机译：急性肺损伤/急性呼吸窘迫综合征（ALLAJRDS）患者的肺液中活性尿激酶（uPA）水平降低，而血浆蛋白酶抑制剂α_2-巨球蛋白（α_2-M）是这些流体的主要成分。由于已有报道描述了qalpha_2-M与uPA在体外形成复合物的能力，因此我们假设alpha2-M可能与uPA在肺中相互作用以调节其生物学活性。对来自ALI / ARDS患者的肺水肿液和肺组织进行了评估是否存在与alpha2-M相关的uPA。在肺泡水肿液以及ALI / ARDS患者的肺中检测到了α2-M和uPA之间的复合物，这些复合物主要位于上皮细胞附近。虽然与α2-M结合的uPA保留了其对低分子量底物的酰胺分解活性，但不受其主要的生理抑制剂纤溶酶原激活剂抑制剂1的抑制。我们还研究了uPA和α2-M之间形成复合物的功能后果体外。我们发现，当将α2-M：uPA复合物添加至人支气管上皮细胞（BEAS-2B）的培养物中时，与添加α2-M：uPA复合物相比，其显着抑制了核因子-kB的激活以及白介素-6和-8的产生。单独使用uPA。我们的发现首次表明，α2-M可调节ALI / ARDS患者中uPA的功能，其作用可能包括uPA纤溶和信号传导活性的调节。

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