Regulation of the Procoagulant Activity within the Bronchoalveolar Compartment of Normal Human Lung

Abstract

The nature of the procoagulant activity of normal bronchoalveolar fluid was examined both qualitatively and quantitatively. Unconcentrated, cell-free lavage freshly obtained from normal volunteers clotted normal plasma in a mean of 84 +/- 20 s. The procoagulant activity was initiated by Factor VII-tissue factor complexes as judged by differential activity in various plasmas genetically deficient in single clotting factors, by neutralization of the procoagulant activity with antibodies to either Factor VII or tissue factor, and by a Factor X activation assay. Preincubation of the lavage with calcium was required to demonstrate Factor VII activity in unconcentrated samples. The cell-free fluid contained about 8,500 thromboplastin units/mg protein, equivalent to a third of the thromboplastin standard and indicating high amounts of cofactor. Quantitation of Factor VII was estimated by functional analysis in coagulation and amidolytic assays with reference to dilutions of normal plasma of known Factor VII concentration. When lavage and diluted plasma were adjusted to yield equivalent amidolytic activities, the average ratio of the Factor VII-clotting activity of the alveolar fluid relative to plasma Factor VII was 19 +/- 7, suggesting the presence of Factor VIIa in lavage. In contrast to previous reports with serum or activated plasma, immunoblots of concentrated lavage revealed only single-chain Factor VII, and 125I-Factor VII added to the fluid was not converted to 125I-Factor VIIa, suggesting a unique control mechanism in the lung compartment which differs from plasma. When equivalent Factor VII amidolytic activities in diluted plasma and cell-free lavage were compared, the rates of Factor Xa formation were very similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

“…The majority of the abnormalities that we previously observed in LTF mice after LPS-mediated injury (2) are recapitulated by absence of TF on the lung epithelium. These findings add to a growing literature showing that coagulation in the airspace is regulated by lung epithelial cells rather than inflammatory cells (3,9,29,31). Our group has previously reported increased levels of TF in pulmonary edema fluid of patients with acute respiratory distress syndrome compared with patients with hydrostatic pulmonary edema (3).…”

From clot to collagen: coagulation peptides in interstitial lung disease

“…A significant proportion of these patients develop fibrotic lesions in the terminal stages of the disease, characterized by increased mesenchymal cell proliferation and collagen deposition. Supporting, but not providing direct evidence for a role for coagulation cascade proteins in these diseases, several studies have shown that there is also increased procoagulant activity in the lungs and bronchoalveolar lavage fluid from patients with these conditions [3,4]. Similar findings have been reported for patients with chronic interstitial lung disease [5], including patients with idiopathic pulmonary fibrosis (IPF), as well as with pulmonary fibrosis associated with systemic sclerosis (SSc) [6,7].…”

Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome.

“…In previous studies, procoagulant activity attributable to components of the extrinsic coagulation pathway has been described in the alveolar compartment of man and experimental animals (2,19,21,23,(43)(44)(45)(46)(47)(48). In addition, fibrinolytic activity attributable to urokinase or urokinase-like PA has been described in BAL and macrophages from the lower respiratory tract of humans and animals (23,41,49,50).…”

“…In addition, fibrinolytic activity attributable to urokinase or urokinase-like PA has been described in BAL and macrophages from the lower respiratory tract of humans and animals (23,41,49,50). Under normal circumstances, little procoagulant activity (21,47,48) and relatively high levels of fibrinolytic activity (23, tologic hallmark of ARDS (3), and can be a prominent feature of the ILD and pneumonitides (1, 2). These observations suggest that the normal homeostasis of coagulation and fibrinolytic processes is disturbed in human lung injury and that conditions that promote fibrin deposition are established in the alveolar compartment.…”