The Plasminogen Activation System in Lung Disease

Abstract

The importance of the plasminogen activator (PA) system in multiple pulmonary disorders has become increasingly apparent as methods to analyze its components have improved. Early investigations discovered that the pulmonary alveolar space is normally a pro-fibrinolytic environment that is diminished in a variety of lung diseases. Interest in these observations was greatly increased when animal experiments revealed that manipulations of the PA system significantly modulated the tissue fibrosis that follows many types of lung injury. In particular, enhancement of PA activity was found to consistently decrease the extent of scarring induced by lung damage. Based upon these early observations, it was hypothesized that fibrin was necessary for the pathogenesis of lung fibrosis, and that an increase in PA activity would reduce collagen accumulation by accelerating the clearance of fibrin from the provisional matrix. However, as is often the case with simple hypotheses, subsequent studies revealed that the actual role of the PA system in pulmonary disease is much more complex. Possible mechanisms beyond fibrinolysis include degradation of other matrix proteins, activation of protease cascades including those involving matrix metalloproteinases, activation and release of growth factors from sites of production and sequestration, and modulation of cell adhesion and motility. In each of these processes, the serpin plasminogen activator inhibitor-1 (PAI-1) plays a central role. For these reasons, it has become apparent that PAI-1 presents an attractive target to influence multiple disease processes within the lung, particularly those that lead to lung fibrosis.

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

“…For example, mice with impaired fibrinolysis caused either by overexpression of a PAI-1 transgene (7) or by targeted deletion of the plasminogen gene (33) develop increased fibrosis after lung injury. In contrast, increasing the activity of the uPA/ plasmin system by the targeted deletion of the PAI-1 gene or by upregulating uPA protects against lung fibrosis following a pulmonary insult (7,32). Only a few studies have investigated the role of the uPA/plasmin system in the development of chronic asthma.…”

Endothelial Cells Recruit Macrophages and Contribute to a Fibrotic Milieu in Bleomycin Lung Injury

“…In addition, Pai-1 was also significantly increased during the fourth week. PAI-1 is the main inhibitor of fibrinolysis, and is speculated to play an additional role in tissue fibrosis through the inhibition of MMP activity and modulation of the inflammatory response (45). These data suggest that endothelial cells may contribute to the proliferation and activation of nearby fibroblasts or pericytes in vivo.…”

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages

“…We next evaluated whether proteolytic collagen degradation in the extracellular matrix was affected by Mfge8 deficiency. We measured mRNA transcript levels of proteases with known roles in lung injury and fibrosis 14 days after bleomycin administration by gene expression array (22)(23)(24). There were no significant differences in levels of metalloproteinase (MMP); TIMP1; cathepsins B, D, L, and K; or urokinase (Supplemental Figure 3A).…”