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(Chest. 1999;116:17S.)
© 1999 American College of Chest Physicians

Hyaluronan Fragments Induce Plasminogen Activator Inhibitor-1 and Inhibit Urokinase Activity in Mouse Alveolar Macrophages*

A Potential Mechanism for Impaired Fibrinolytic Activity in Acute Lung Injury

M. R. Horton, MD; M. A. Olman, MD and P. W. Noble, MD

* From the Divisions of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, University of Alabama, Birmingham, AL, and Yale University School of Medicine, New Haven, CT, and the VA-CT Healthcare System, West Haven, CT.

Correspondence to: Paul Noble, MD, Yale University School of Medicine, LCI 105, 333 Cedar St, PO Box 208057, New Haven, CT 06520-8057

Impaired fibrinolytic activity within the lung is an important component of acute lung injury. Recent evidence has suggested that the inability to resorb fibrin may contribute to increased lung fibrosis in animal models of acute lung injury. Overexpression of plasminogen activator inhibitor-1 (PAI-1) in transgenic mice resulted in increased lung collagen deposition following treatment with bleomycin.1

Macrophages are an important source of PAI-1 activity, but the mechanisms that regulate PAI-1 expression in alveolar macrophages are poorly understood. Turnover of the extracellular matrix has been shown to be an early event in acute lung injury. One component of the extracellular matrix that has been shown to be increased in animal models of acute lung injury and in patients with ARDS is the glycosaminoglycan hyaluronan (HA).

Recent work from our laboratory has shown that lower-molecular-weight fragments of HA can induce the expression of a number of inflammatory mediators in macrophages.2,3 We hypothesized that HA fragments may induce PAI-1 activity and down-regulate fibrinolytic activity in mouse alveolar macrophages. To test this hypothesis, we stimulated a mouse alveolar macrophage cell line (MH-S) with HA fragments over time, isolated messenger RNA, and examined PAI-1 and urokinase expression by Northern analysis. HA fragments induced PAI-1 messenger RNA with a maximal response between 3 to 6 h. HA also inhibited the baseline urokinase expression. Western blot analysis demonstrated up-regulation of PAI-1 protein following exposure of MH-S cells to HA fragments. Importantly, inhibition of fibrinolytic activity was demonstrated by zymography. Together, these data suggest that one mechanism for impaired fibrinolytic activity in acute lung injury may be through the effects of HA fragments on alveolar macrophage PAI-1 expression.

References

  1. Eitzman, DT, McCoy, RD, Zheng, X, et al (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 97,232-237
  2. McKee, CM, Penno, MB, Cowman, M, et al (1996) Hyaluronan fragments induce chemokine gene expression in alveolar macrophages: the role of HA size and CD44. J Clin Invest 98,2403-2413
  3. McKee, CM, Lowenstein, C, Horton, MR, et al (1997) Hyaluronan fragments induce nitric oxide synthase in murine macrophages through an NF-{kappa}B-dependent mechanism. J Biol Chem 272,8013-8018




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Right arrow Articles by Horton, M. R.
Right arrow Articles by Noble, P. W.

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