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.

Asthma and coagulation

“…6,8 Asthma is associated with inhibition of fibrinolysis in the airways, primarily because of enhanced production of PAI-1. 78 PAI-1 levels were increased in sputum of patients with asthma 17,79 and in BAL fluid of rodents sensitized and challenged with ovalbumin, 10,80,81 which was accompanied by decreased plasminogen activator activity. 10 Administration of uPA improved various features characteristic for asthma, including airway hyperresponsiveness and subepithelial fibrosis in the lungs of mice exposed to ovalbumin 82 ; similarly, inhalation of aerosolized tPA reduced airway hyper-responisveness in this model.…”

“…81,83 In addition, transcription of PAI-1 was highly up-regulated in 84 and mast celldeficient mice had approximately 50% less PAI-1 in their airways compared with normal mice after ovalbumin challenge in vivo. 78 PAI-1 has been implicated as a mediator of the allergic immune response: in a murine allergic rhinitis model, PAI-1-deficient mice showed a suppressed Th2 response and fewer symptoms. 85 In addition, PAI-1-deficient mice displayed a reduced airway hyper-responsiveness in the ovalbumin-induced allergic lung inflammation model.…”

Concentrations of plasminogen activator inhibitor-1 (PAI-1) and urokinase plasminogen activator (uPA) in induced sputum of asthma patients after allergen challenge.

“…However, it seems that plasma is not the predominant source of sputum PAI-1 because elevated sputum levels of PAI-1 are still observed 24 hours after the challenge, while at that time point plasma levels within the circulation return to baseline values [17]. Synthesis of both PAI-1 and uPA is rapidly induced by many factors including cytokines, growth factors and hormones [5,6]. Several potential sources of PAI-1 and uPA in the airways of asthmatic patients have to be considered.…”

“…Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) play an important role in regulation of the inflammatory response and tissue remodeling [5,6]. In an animal asthma model either suppression of PAI-1 expression by knockout of the PAI-1 gene or delivery of exogenous uPA leads to decreased airway remodeling and decreased airway hyperresponsiveness [7][8][9].…”

Bronchial Asthma and Obesity in Childhood

“…Plasminogen activator inhibitor (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator and is thus the major physiological inhibitor both of fibrinolysis and of plasmin activation (34). Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodeling, airway hyper-responsiveness (AHR), and allergic inflammation (27). Adipocytes produce and secrete PAI-1 and serum levels of PAI-1 are increased in the obese and decrease with Increased serum PAI-1 could have effects in the airways that predispose towards hyper-responsiveness.…”