Fibrosis causes irreversible damage to lung structure and function in restrictive
lung diseases such as
idiopathic pulmonary fibrosis (IPF). Extravascular coagulation involving
fibrin formation in the intra-alveolar compartment is postulated to have a pivotal role in the development of
pulmonary fibrosis, serving as a provisional matrix for migrating fibroblasts. Furthermore,
proteases of the coagulation and
plasminogen activation (plasminergic) systems that form and breakdown
fibrin respectively directly contribute to
pulmonary fibrosis. The
coagulants,
thrombin and
factor Xa (FXa) evoke fibrogenic effects via cleavage of the N-terminus of
protease-activated receptors (PARs). Whilst the formation and activity of
plasmin, the principle plasminergic mediator is suppressed in the airspaces of patients with IPF, localized increases are likely to occur in the lung interstitium.
Plasmin-evoked proteolytic activation of
factor XII (FXII), matrix
metalloproteases (
MMPs) and latent, matrix-bound
growth factors such as
epidermal growth factor (
EGF) indirectly implicate
plasmin in
pulmonary fibrosis. Another plasminergic
protease,
urokinase plasminogen activator (uPA) is associated with regions of
fibrosis in the remodelled lung of IPF patients and elicits fibrogenic activity via binding its
receptor (uPAR).
Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to
pulmonary fibrosis in a manner that involves
vitronectin binding. This review describes the mechanisms by which components of the two systems primarily involved in
fibrin homeostasis contribute to interstitial
fibrosis, with a particular focus on IPF. Selectively targeting the receptor-mediated mechanisms of
coagulant and plasminergic
proteases may limit
pulmonary fibrosis, without the
bleeding complications associated with conventional anti-
coagulant and
thrombolytic therapies.