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1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA
2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA; VA Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: jsavov{at}duke.edu.
To examine the role of the fibrinolytic system in lipopolysaccharide (LPS) induced airway disease, we compared the affect of a chronic LPS challenge in plasminogen activator inhibitor deficient (C57BL/6JPAI-1-/-) mice and wild-type (WT) C57BL/6J mice. Physiologic and biologic assessments were performed before (n=24), immediately after (n=12), and 4 wk after (n=12) the end of an 8 wk exposure to either LPS or saline (control). Immediately following the 8 week LPS exposure, WT mice had increased estimates of airway reactivity to methacholine when compared to C57BL/6JPAI-1-/- mice, however, airway inflammation was similar in both C57BL/6JPAI-1-/- and WT LPS exposed groups. Significant increases in both active TGF-
1 and active MMP-9 was detected following LPS exposure in WT mice but not in C57BL/6JPAI-1-/- mice. C57BL/6JPAI-1-/- animals showed significantly less TGF-1 (total and active) in the lavage and higher MMP-9 in the lung tissue than WT mice at the end of the exposure as well as 4 wk later. Following LPS exposure, both WT and C57BL/6JPAI-1-/- mice had substantial expansion of the subepithelial area of the medium (d=90-129µm) and large (d>129µm) size airways when compared to saline-exposed mice. Subepithelial fibrin deposition was prevalent in WT mice, but greatly diminished in C57BL/6JPAI-1-/-. PAI-1 expression by non-ciliated bronchial epithelial cells was enhanced in the airways of LPS exposed WT mice when compared to the saline-exposed group. Four weeks following inhalation of LPS the increased airway reactivity and the expansion of the subepithelial area in the medium and large size airways persisted in WT mice, but not in the C57BL/6JPAI-1-/- mice. We conclude that an active fibrinolytic system can substantially alter the development and resolution of the postinflammatory airway remodeling that is observed following chronic inhalation of LPS.
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