Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse.

Abstract

Bleomycin-induced lung injury is an established murine model of human pulmonary fibrosis. Although procoagulant molecules (e.g., tissue factor [TF]) and fibrinolytic components (e.g., urokinase [u-PA] and type 1 plasminogen activator inhibitor [PAI-1]) have been detected in alveolar fluid from injured lungs, the origin of these molecules remains unknown. We therefore examined the expression of procoagulant and fibrinolytic components in relation to the distribution of parenchymal fibrin in bleomycin-injured lungs. Extravascular fibrin localized to the alveolar and extracellular matrix in injured lung tissue. Injured lung tissue extracts contained elevated levels of PAI-i activity and decreased levels of u-PA activity. Whole lung PAT-i and TF mRNAs were dramatically induced by lung injury. In situ hybridization of injured lungs revealed that PAI-1, u-PA, and TF mRNAs were induced within the fibrin-rich fibroproliferative lesions, primarily in fibroblast-like and macrophagelike cells, respectively, while TF mRNA was also induced in perilesional alveolar cells. Taken together, these observations suggest that the induction of PAT-i and TF gene expression plays an important role in the formation and persistence of extracellular fibrin in bleomycin injured murine lungs. (J. Clin. Invest. 1995. 96:1621-1630

From clot to collagen: coagulation peptides in interstitial lung disease

“…For example, thrombin has been shown to be increased and act as a potent fibroblast mitogen in BAL fluid obtained from rats developing fibrosis following bleomycin administration [10]. More recently, TF expression was shown to be increased at sites characterized by persistent fibrin deposition and fibroproliferation in mice following a similar administration of bleomycin [11].…”

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

“…Due to the diverse functions of these proteases and their degradation products, fibrinolytic activity is tightly regulated by a number of protease inhibitors, in particular PAs by plasminogen activator inhibitors (PAIs) and plasmin by the serpin inhibitors, ␣ 2 -antiplasmin, ␣ 1 -antitrypsin, and ␣ 2 -macroglobulin. 5 Although deposition of a fibrin matrix is fundamental to normal repair, it is also a common consequence of a number of pathological disorders such as atherosclerosis, 9 restenosis, 10 postoperative adhesions, 11 pulmonary fibrosis, 12 and tumorigenesis. 13 In such conditions, the presence of fibrin is often integrally associated with excess collagen accumulation and fibrosis.…”

Plasminogen activator inhibitor-1 is a major stress-regulated gene: Implications for stress-induced thrombosis in aged individuals

“…Elevated levels of plasma PAI-1 are observed in a variety of thrombotic conditions (15), including myocardial infarction (16), deep vein thrombosis (17), and disseminated intravascular coagulation (18). Increased PAI-1 gene expression also was demonstrated in several specific histopathologies [e.g., lung fibrosis (19), glomerulonephritis (20,21), and atherosclerosis (22,23)]. In obese humans, increased plasma PAI-1 levels correlated with the amounts of visceral fat (24), suggesting that the adipose tissue is the primary source of PAI-1 in this condition (25).…”