To review: a) the role of extravascular
fibrin deposition in the pathogenesis of
acute lung injury; b) the abnormalities in the coagulation and fibrinolysis pathways that promote
fibrin deposition in the acutely injured lung; and c) the pathways that contribute to the regulation of the fibrinolytic system via the lung epithelium, including newly recognized posttranscriptional and
urokinase-dependent pathways. Another objective was to determine how novel
anticoagulant or fibrinolytic strategies may be used to protect against acute
inflammation or accelerated
fibrosis in
acute lung injury.
DATA SOURCES: Published medical literature.
DATA SUMMARY: Alveolar
fibrin deposition is characteristic of diverse forms of
acute lung injury. Intravascular
thrombosis or
disseminated intravascular coagulation can also occur in the acutely injured lung. Extravascular
fibrin deposition promotes lung dysfunction and the acute inflammatory response. In addition, transitional
fibrin in the alveolar compartment undergoes remodeling leading to accelerated
pulmonary fibrosis similar to the events associated with wound healing, or desmoplasia associated with solid
neoplasms. In
acute lung injury, alveolar
fibrin deposition is potentiated by consistent changes in endogenous coagulation and fibrinolytic pathways. Procoagulant activity is increased in conjunction with depression of fibrinolytic activity in the alveolar compartment. Initiation of the procoagulant response occurs as a result of local overexpression of
tissue factor associated with
factor VII. Depression of fibrinolytic activity occurs as a result of inhibition of
urokinase plasminogen activator (uPA) by
plasminogen activators, or series inhibition of
plasmin by
antiplasmins. Locally increased amplification of
plasminogen activator inhibitor-1 (PAI-1) is largely responsible for this
fibrinolytic defect. Newly described pathways by which lung epithelial cells regulate expression of uPA, its
receptor uPAR, and
PAI-1 at the posttranscriptional level have been identified. These pathways operate by cis-trans interactions between
mRNA binding proteins; regulatory sequences within these mRNAs control their stability. The regulatory mechanisms seem to involve multiple
protein-
mRNA interactions, and the phosphorylation state of the
proteins appears to determine whether complex formation of, or dissociation from, the regulatory sequences occurs. uPA is capable of inducing its own expression in lung epithelial cells as well as that of uPAR and PAI-1-the effects involve posttranscriptional regulatory components. These and related observations have led to the implementation of
anticoagulant or fibrinolytic strategies to protect the lung against
acute lung injury. The success of new fibrinolytic strategies to block pleural loculation suggests that a similar approach might be used to prevent accelerated
pulmonary fibrosis, which can occur in association with many forms of
acute lung injury.
CONCLUSIONS: Disordered coagulation and fibrinolysis promote extravascular
fibrin deposition in
acute lung injury. It is this deposition that characterizes
acute lung injury and repair. Expression of uPA, uPAR, and
PAI-1 by the lung epithelium, as well as the ability of uPA to induce other components of the fibrinolytic system, involves posttranscriptional regulation. These pathways may contribute to disordered
fibrin turnover in the injured lung. The success of
anticoagulant or fibrinolytic strategies designed to reverse the abnormalities of local
fibrin turnover in
acute lung injury supports the inference that abnormalities of coagulation, fibrinolysis, and
fibrin deposition have a critical role in the pathogenesis of
acute lung injury.