Possible role of the 4G/5G polymorphism of the plasminogen activator inhibitor I gene in the development of asthma

Asthma represents a chronic inflammatory process of the airways. The plasmi nogen activator inhibitor I gene (PAI1) has an essential role in promoting fibrosis after inflammation. The tissue-type, plasminogen activator and uro kinase-type plasminogen activator convert plasminogen to plasmin, which enh ances proteolytic degradation of the extracellular matrix (ECM). Among the inhibitors of plasminogen activators, PAI-I is the most important in the pr ocess of lunar fibrosis(1) PAI-1-overexpressing mice underwent severe lung injury and deposition of ECM after bleomycin challenge, whereas PAI-1-defic ient mice were protected against such fibrotic reactions.(2) these reaction s.2 These findings show that PAI-1 is closely associated with fibrosis and the accumulation of ECM after lung injury or inflammation. We previously re ported that the PAT1 gene is induced in lung mast cells in asthmatic subjec ts.(3) These findings suggest that PAI-1 could contribute to tissue remodel ing and subsequent fibrosis in asthma. The PAI1 gene has variation in the p romoter region on the basis. of a single guanosine insertion-deletion (5G o r 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 nuc lear factor KB group of transcription factors, and this binding site is abs ent in the *4G allele.(4) After stimulation with IL-1, HepG2 cells. transfe cted with the *4G allele produce 6 times more PAI-1 mRNA than these with th e *5G allele. These data suggest a functional role of the. 4G/5G polymorphi sm 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 sugg est a possible role of the PAI1 gene and the 4G polymorphism in the pathoph ysiology of asthma.