Abstract
BackgroundPulmonary fibrosis is a progressive and lethal disease characterized by damage to the lung parenchyma with excess extracellular matrix deposition. The involvement of endothelial cells in fibrosis development is unclear.MethodsWe isolated pulmonary endothelial cells, using a magnetic-activated cell sorting system, from mice with pulmonary fibrosis induced by intratracheal bleomycin. We characterized endothelial cells isolated at various times in the course of pulmonary fibrosis development.ResultsInflammatory cell infiltration was observed at 7 days after bleomycin administration, and fibrotic changes with increased collagen content were observed on day 21. Endothelial cells were isolated at these two timepoints. Levels of von Willebrand factor, plasminogen activator inhibitor-1 and matrix metalloproteinase-12 were elevated in lung endothelial cells isolated from bleomycin-treated mice at days 7 and 21. This indicated that intratracheal bleomycin administration induced endothelium injury. Expression of fibrogenic mediators, transforming growth factor (TGF)-β, connective tissue growth factor and platelet-derived growth factor-C was elevated in the cells from bleomycin-treated, compared with untreated, lungs. When endothelial cells were treated with TGF-β, α-smooth muscle actin (SMA) expression and collagen production were increased only in those cells from bleomycin-treated mouse lungs. Thapsigargin-induced prostaglandin I2 and nitric oxide production, decreased in endothelial cells from bleomycin-treated mouse lungs, compared with controls, was further suppressed by TGF-β.ConclusionBleomycin administration induced functional changes in lung endothelial cells, indicating potential involvement of endothelium in pulmonary fibrogenesis.
Highlights
Pulmonary fibrosis is a progressive and lethal disease characterized by damage to the lung parenchyma with excess extracellular matrix deposition
Intratracheal bleomycin administration induced damage and subsequent pulmonary fibrosis Intratracheal administration of bleomycin to mice using a Microsprayer Aerosolizer led to a gradual weight decrease, with peak weight loss at about day 7, significantly lower than saline-treated mice
Pulmonary endothelial cells were injured by bleomycin administration As markers of endothelial injury, we examined expression of von Willebrand factor, plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase (MMP)-12 (Table 1)
Summary
Pulmonary fibrosis is a progressive and lethal disease characterized by damage to the lung parenchyma with excess extracellular matrix deposition. Interstitial lung diseases (ILDs) and pulmonary fibrosis are characterized by damage to the lung parenchyma with varying patterns of inflammation and fibrosis [1]. It is currently believed that epithelial cell injury initiates the pathology and is followed by a mild inflammatory response [2,3,4]. Takabatake et al demonstrated pulmonary microvascular endothelial cell injury during a fibrotic process in patients with ILDs [9]. In patients with ILDs, the rate of 123I-metaiodobenzylguanidine washout from the lungs, reflecting pulmonary endothelial cell injury, was lower than in normal controls
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