The Role of Coagulation and Fibrinolysis in the Pathogenesis of Acute Lung Injury

J.   A.   Bastarache; L.      Wang; L.   B.   Ware

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and life threatening causes of acute respiratory failure throughout the world. Much is known about the pathogenesis of this devastating problem yet specific pharmacologic therapies are lacking. In recent years many investigators have demonstrated that the alveolar compartment in ALI/ARDS is a pro-coagulant, anti-fibrinolytic environment. With the clinical success of modulation of coagulation abnormalities in severe sepsis with administration of Drotecogin alfa (activated protein C), the importance of the coagulation in the pathogenesis of human disease is becoming clear. In this full length review we will summarize the current literature in the field of coagulation and fibrinolytic abnormalities in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). We will focus on both in vitro and in vivo studies of the role of the coagulation cascade in lung injury at the level of initiation of coagulation through modulation of tissue factor (TF) and tissue factor pathway inhibitor (TFPI), propagation of coagulation via protein C and thrombomodulin (TM), and resolution through thrombolysis by plasminogen activator (PA), plasminogen activator receptor (PAR) and plasminogen activator inhibitor-1 (PAI-1). We will highlight some of our own work in this field as well as discuss important contributions from other laboratories. In addition, we will discuss the relevant cell studies that may potentially lead to new therapies.

Keywords: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS), coagulation, fibrinolysis, tissue factor (TF), tissue factor pathway inhibitor (TFPI), Protein C, Thrombomodulin, endothelial protein c receptor (EPCR), plasminogen activator (uPA, tPA)