Possible role of the 4G/5G polymorphism of the plasminogen activator inhibitor I gene in the development of asthma
Possible role of the 4G/5G polymorphism of the plasminogen activator inhibitor I gene in the development of asthma
复制标题
DOI：
10.1067/mai.2001.117260
复制
发表时间：
2001-08-01
影响因子：
14.2
通讯作者：
Oh, CK
中科院分区：
文献类型：
--
作者：
Cho, SH;Hall, IP;Oh, CK
哮喘是气道的慢性炎症过程。纤溶酶原激活物抑制剂I基因（PAI 1）在炎症后促进纤维化中具有重要作用。组织型纤溶酶原激活物和尿激酶型纤溶酶原激活物将纤溶酶原转化为纤溶酶，这增强了细胞外基质（ECM）的蛋白水解降解。在纤溶酶原激活物的抑制剂中，PAI-1在月球纤维化的过程中是最重要的（1）派-1过表达的小鼠在博来霉素攻击后发生严重的肺损伤和ECM沉积，而派-1缺陷的小鼠对这些纤维化反应具有保护作用。(2)这些发现表明派-1与肺损伤或炎症后的纤维化和ECM积聚密切相关。我们以前报道过，在哮喘患者的肺肥大细胞中，PAT 1基因被诱导。(3)这些发现表明派-1可能有助于哮喘的组织重塑和随后的纤维化。PAI 1基因在启动子区有变异。单个鸟苷插入-缺失（5G或4G）;（4，5）和 *4G等位基因与血浆派-1水平升高相关。（5，6）体外实验最初表明，*5G等位基因含有可能与核因子KB组转录因子相关的蛋白质的额外结合位点，并且该结合位点在 *4G等位基因中不存在。(4)经IL-1刺激后，HepG 2细胞。*4G等位基因转染的细胞产生的派-1 mRNA是 *5G等位基因转染的细胞的6倍。这些数据表明，功能的作用。4G/5G多态性在对细胞因子的应答中，*4G等位基因与增强的基因表达相关。在本研究中，我们证明 *4G等位基因优先传递给哮喘儿童。这些数据表明PAI 1基因和4G多态性在哮喘的病理生理学中可能发挥作用。
Asthma represents a chronic inflammatory process of the airways. The plasminogen activator inhibitor I gene (PAI1) has an essential role in promoting fibrosis after inflammation. The tissue-type, plasminogen activator and urokinase-type plasminogen activator convert plasminogen to plasmin, which enhances proteolytic degradation of the extracellular matrix (ECM). Among the inhibitors of plasminogen activators, PAI-I is the most important in the process of lunar fibrosis(1) PAI-1-overexpressing mice underwent severe lung injury and deposition of ECM after bleomycin challenge, whereas PAI-1-deficient mice were protected against such fibrotic reactions.(2) these reactions.2 These findings show that PAI-1 is closely associated with fibrosis and the accumulation of ECM after lung injury or inflammation. We previously reported that the PAT1 gene is induced in lung mast cells in asthmatic subjects.(3) These findings suggest that PAI-1 could contribute to tissue remodeling and subsequent fibrosis in asthma. The PAI1 gene has variation in the promoter region on the basis. of a single guanosine insertion-deletion (5G or 4G);(4,5) and the *4G allele, is, correlated with increased plasma PAI-1 levels.(5,6) In vitro experiments have initially shown that the *5G allele contains an additional binding site for a protein likely related to the nuclear factor KB group of transcription factors, and this binding site is absent in the *4G allele.(4) After stimulation with IL-1, HepG2 cells. transfected with the *4G allele produce 6 times more PAI-1 mRNA than these with the *5G allele. These data suggest a functional role of the. 4G/5G polymorphism in the response to cytokines, with the,*4G allele being associated with enhanced gene expression. In the present study we demonstrate that the *4G allele is preferentially transmitted to asthmatic children. These data suggest a possible role of the PAI1 gene and the 4G polymorphism in the pathophysiology of asthma.