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Modulation of Intra-alveolar Fibrin Deposition by the Alveolar Epithelium In Acute Lung Injury: Clinical and Experimental Evidence

¹ Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee; and ² Cardiovascular Research Institute and Departments of Medicine and Anesthesia, University of California, San Francisco, California

Correspondence and requests for reprints should be addressed to Lorraine B. Ware, M.D., T1218 MCN, 1161 21^st Avenue, S. Nashville, TN 37232-2650. E-mail: lorraine.ware{at}vanderbilt.edu

Intra-alveolar fibrin deposition is a pathological hallmark of acute lung injury (ALI). However, the mechanisms that control alveolar fibrin deposition are poorly understood. Increasing evidence suggests that inflammation and coagulation are linked and amplify each other. Thus, it is important to understand the mechanisms that modulate fibrin deposition and dissolution in the airspaces in ALI. In a series of clinical and in vitro studies we have investigated the hypothesis that the alveolar epithelium is a key modulator of intra-alveolar fibrin deposition. In undiluted pulmonary edema fluid from patients with ALI, levels of tissue factor (TF), thrombomodulin (TM), the endothelial protein C receptor (EPCR), and plasminogen activator inhibitor-1 (PAI-1) were much higher than simultaneous plasma levels, suggesting an intra-alveolar source. Furthermore, higher levels of these proteins were associated with adverse clinical outcomes, highlighting the prognostic and pathogenetic importance of intra-alveolar coagulation and impaired alveolar fibrinolysis in ALI. To investigate whether the alveolar epithelium is a local source of these coagulation and fibrinolytic proteins in the airspaces, we tested the capacity of distal lung epithelial cells (DLECs including A549, 1° human small airway epithelial cells, and 1° human type II cells) to modulate coagulation and fibrinolysis. In vitro, DLECs express active TF, activate the extrinsic coagulation cascade, activate protein C through expression of TM and EPCR, and can modulate fibrinolysis through expression of PAI-1. Exposure of DLECs to a pro-inflammatory stimulus (TNF-, IL-1β, IFN-) alters the DLECs from an anticoagulant/profibrinolytic to a procoagulant/antifibrinolytic phenotype, and also triggers (1) release of procoagulant TF-containing microparticles, (2) metalloproteolytic cleavage of TM and EPCR from the cell surface, and (3) secretion of PAI-1 from the epithelial cells. These findings provide evidence that the alveolar epithelium actively modulates fibrin deposition and dissolution in the lung, a process that is fundamentally altered by the pro-inflammatory milieu of the acutely injured lung.

FOOTNOTES

Supported by NIH HL081332 (L.B.W.) and HL58156 (M.A.M.).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 29, 2007; accepted in final form October 16, 2007)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ware, L. B. Articles by Matthay, M. A. PubMed Articles by Ware, L. B. Articles by Matthay, M. A.