Abstract
BackgroundRecent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis. The aim of our study was to assess whether endostatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in rats.MethodsThe rats were randomly divided into five experimental groups: (A) saline only, (B) BLM only, (C) BLM plus early endostatin treatment, (D) BLM plus late endostatin treatment, and (F) BLM plus whole-course endostatin treatment. We investigated the microvascular density (MVD), inflammatory response and alveolar epithelial cell apoptosis in rat lungs in each group at different phases of disease development.ResultsEarly endostatin administration attenuated fibrotic changes in BLM-induced pulmonary fibrosis in rats. Endostatin treatment decreased MVD by inhibiting the expression of VEGF/VEGFR-2 (Flk-1) and the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Endostatin treatment also decreased the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid during the early inflammatory phase of BLM-induced pulmonary fibrosis. In addition, the levels of tumour necrosis factor-α (TNF-α) and transforming growth factor β1 (TGF-β1) were reduced by endostatin treatment. Furthermore, endostatin decreased alveolar type II cell apoptosis and had an epithelium-protective effect. These might be the mechanism underlying the preventive effect of endostatin on pulmonary fibrosis.ConclusionsOur findings suggest that endostatin treatment inhibits the increased MVD, inflammation and alveolar epithelial cell apoptosis, consequently ameliorating BLM-induced pulmonary fibrosis in rats.
Highlights
Recent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis
We show that endostatin prevents BLM-induced pulmonary fibrosis in rats through the reduction of aberrant angiogenesis, proinflammatory cytokine production and alveolar epithelial cell apoptosis
Effect of endostatin on BLM-induced pulmonary fibrosis We evaluated the effect of endostatin treatment in the BLM-induced lung fibrosis model
Summary
Recent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Among the numerous cytokines related to angiogenesis, vascular endothelial growth factor (VEGF) has been recognised as an important regulator of angiogenesis and a major enhancer of vascular permeability in several types of inflammatory lesions [10,14]. It is essential for endothelial cell survival, proliferation and tube formation. VEGF regulates endothelial cell morphology and activates multiple signal transduction pathways, including extracellular signal–regulated kinase (ERK1/2) [16], which is involved in regulating the angiogenesis and inflammation response in the lung. VEGF inhibition is being tested as a strategy for the prevention of angiogenesis and vascular leakage in pulmonary fibrosis
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