[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Sep 2001 · Journal of Allergy and Clinical Immunology