Elsevier

Thrombosis Research

Volume 77, Issue 6, 15 March 1995, Pages 493-504
Thrombosis Research

Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis

https://doi.org/10.1016/0049-3848(95)00025-9Get rights and content

Abstract

To elucidate the pathophysiology of idiopathic pulmonary fibrosis (IPF), we examined procoagulant (tissue factor:TF), fibrinolytic (tissue type plasminogen activator:t-PA and urokinase type plasminogen activator:u-PA) and antifibrinolytic (plasminogen activator inhibitor-1:PAI-1 and PAI-2) activities in bronchoalveolar lavage (BAL) supernatant fluids and BAL cell lysates obtained from IPF patients. The results indicated that TF levels in BAL supernatant fluids from IPF patients were higher than those of normal subjects, especially in patients with progressive disease, suggesting that TF levels in the lung correlate with disease activity. PAI-1 levels in BAL supernatant fluids were significantly higher in IPF patients than in normal subjects (1.7 ± 4.1 vs 0 ng/mg protein). PAI-2 levels in BAL cell lysates were also significantly higher in IPF patients than those in normal subjects (14.4 ± 12.2 vs 3.0 ± 3.0 ng/mg protein). However, u-PA levels in both BAL supernatant fluids and BAL cell lysates did not differ between the two groups. These observations suggest that u-PA inhibition exceeded u-PA activity in alveolar lining fluid resulting in an antifibrinolytic condition. Immunohistochemical analysis showed that TF was intensely stained in cuboidal epithelial cells and PAIs were positively stained in alveolar macrophages (AMs) and cuboidal epithelial cells, suggesting that cuboidal epithelial cells as well as AMs contribute to the increased procoagulant and antifibrinolytic activities in the lungs of IPF patients.

References (32)

  • CarringtonC.B. et al.

    Natural history and treated course of usual and desquamative interstitial pneumonia

    New Eng J Med

    (1978)
  • KatzensteinA-L.A. et al.

    Surgical Pathology of Non-Neoplastic Lung Disease

  • ColbyT.L. et al.
  • BittermanP.B. et al.

    Role of fibronectin as a growth factor for fibroblasts

    J Cell Biol

    (1983)
  • RennardS.I. et al.

    Production of fibronectin by the human alveolar macrophage: Mechanism for the recruitment of fibroblasts to sites of tissue injury in interstitial lung diseases

  • ChapmanH.A. et al.

    Human alveolar macrophages synthesize factor VII in vitro. Possible role in interstitial lung disease

    J Clin Invest

    (1985)
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