Barazzone C, Belin D, Piguet P F, Vassalli J D, Sappino A P
Department of Pediatrics, University of Geneva, Switzerland.
J Clin Invest. 1996 Dec 15;98(12):2666-73. doi: 10.1172/JCI119089.
Hyperoxia-induced lung disease is associated with prominent intraalveolar fibrin deposition. Fibrin turnover is tightly regulated by the concerted action of proteases and antiproteases, and inhibition of plasmin-mediated proteolysis could account for fibrin accumulation in lung alveoli. We show here that lungs of mice exposed to hyperoxia overproduce plasminogen activator inhibitor-1 (PAI-1), and that PAI-1 upregulation impairs fibrinolytic activity in the alveolar compartment. To explore whether increased PAI-1 production is a causal or only a correlative event for impaired intraalveolar fibrinolysis and the development of hyaline membrane disease, we studied mice genetically deficient in PAI-1. We found that these mice fail to develop intraalveolar fibrin deposits in response to hyperoxia and that they are more resistant to the lethal effects of hyperoxic stress. These observations provide clear and novel evidence for the pathogenic contribution of PAI-1 in the development of hyaline membrane disease. They identify PAI-1 as a major deleterious mediator of hyperoxic lung injury.
高氧诱导的肺部疾病与肺泡内显著的纤维蛋白沉积有关。纤维蛋白的周转受到蛋白酶和抗蛋白酶协同作用的严格调控，纤溶酶介导的蛋白水解作用受到抑制可能是肺泡内纤维蛋白积聚的原因。我们在此表明，暴露于高氧环境的小鼠肺脏会过度产生纤溶酶原激活物抑制剂-1（PAI-1），并且PAI-1的上调会损害肺泡腔室中的纤溶活性。为了探究PAI-1产量增加是肺泡内纤溶功能受损和透明膜病发展的因果事件还是仅仅是相关事件，我们研究了PAI-1基因缺陷的小鼠。我们发现这些小鼠在暴露于高氧环境时不会形成肺泡内纤维蛋白沉积，并且它们对高氧应激的致死效应更具抵抗力。这些观察结果为PAI-1在透明膜病发展中的致病作用提供了清晰而新颖的证据。它们将PAI-1确定为高氧性肺损伤的主要有害介质。
