*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
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
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.
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