Plasminogen activator inhibitor‐1 and asthma: role in the pathogenesis and molecular regulation

Abstract

Plasminogen activator inhibitor (PAI)‐1 is a major inhibitor of the fibrinolytic system. PAI‐1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI‐1 production. Recent studies suggest that PAI‐1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at −675 bp of the PAI‐1 gene is the major genetic determinant of PAI‐1 expression. Plasma PAI‐1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI‐1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI‐1 promoter with the 4G allele renders higher transcription activity than the PAI‐1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele‐mediated higher PAI‐1 expression is associated with greater binding of upstream stimulatory factor‐1 to the E‐box adjacent to the 4G site (E‐4G) than to the E‐5G. In summary, PAI‐1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI‐1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI‐1‐associated diseases.