Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 285, Issue 4, Pages L940-L948Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00102.2003
Keywords
airway remodeling; lung inflammation; transforming growth factor-beta 1; matrix metalloproteinase-9; plasminogen activator inhibitor
Categories
Funding
- NHLBI NIH HHS [HL-66604, HL-66611, HL-67467] Funding Source: Medline
- NIEHS NIH HHS [ES-11375, ES-09607, ES-07498] Funding Source: Medline
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To examine the role of the fibrinolytic system in LPS-induced airway disease, we compared the effect of a chronic LPS challenge in plasminogen activator inhibitor-deficient (C57BL/6J(PAI-1-/-)) mice and wild-type (WT) C57BL/6J mice. Physiological and biological assessments were performed, immediately after, and 4 wk after an 8-wk exposure to LPS or saline. Immediately after the LPS exposure, WT mice had increased estimates of airway reactivity to methacholine compared with C57BL/6J(PAI-1-/-) mice; however, airway inflammation was similar in both LPS-exposed groups. Significant increases in both active transforming growth factor (TGF)-beta1 and active matrix metalloproteinase (MMP)-9 was detected after LPS exposure in WT but not C57BL/6J(PAI-1-/-) mice. C57BL/6J(PAI-1-/-) mice showed significantly less TGF-beta1 in the lavage and higher MMP-9 in the lung tissue than WT mice at the end of exposure and 4 wk later. After LPS exposure, both WT and C57BL/6J(PAI-1-/-) mice had substantial expansion of the subepithelial area of the medium [diameter (d) = 90-129 mum]- and large (d > 129 mum)-size airways when compared with saline-exposed mice. Subepithelial fibrin deposition was prevalent in WT mice but diminished in C57BL/6J(PAI-1-/-). PAI-1 expression by nonciliated bronchial epithelial cells was enhanced in LPS-exposed WT mice compared with the saline-exposed group. Four weeks after LPS inhalation, airway hyperreactivity and the expansion of the subepithelial area in the medium and large airways persisted in WT but not C57BL/6J(PAI-1-/-) mice. We conclude that an active fibrinolytic system can substantially alter the development and resolution of the postinflammatory airway remodeling observed after chronic LPS inhalation.
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