Remodeling of alveolar capillaries in the lungs of idiopathic pulmonary fibrosis. New approach to fibrogenesis and clinical application

点击翻译按钮获取中文摘要

To clarify apparent contradictions in vascular remodeling in the lungs of idiopathic pulmonary fibrosis (IPF), we evaluated the vascular density (VD) within the alveolar septa in the lungs of seven IPF patients in relation to the various degrees of alveolar fibrosis, scored from 1 to 8. CD34 appeared as an excellent marker of alveolar capillary endothelial cells, and VD, determined as the relative ratio of the capillary area to the total area of alveolar walls, was significantly higher at low grades of fibrosis (scores 1&2, 23.4±1.17%) than in control lungs (12.3±1.62%, p<0.0001). VEGF and IL-8, potent angiogenic factors, were extremely produced by the alveolar epithelial cells lining the vascularized alveolar walls, and an augmented expression of angiotensin converting enzyme (ACE) was observed in these increased capillary endothelial cells. In contrast, VD gradually decreased as the degree of fibrosis increased and was lower than that of the control lungs in the most extensively fibrous lesions (scores 7&8, 5.10±0.54%, p=0.0003). These results exhibited the increase of alveolar capillaries only in the early lesions of the lungs of IPF, which would contribute to fibroproliferation by producing an augmented level of ACE.In addition, we evaluate in this study (1) the effect of angiotensin II (AII), produced by angiotensin converting enzyme augmentedly expressed in the increased capillary endothelial cells, and (2) the effect of angiogenesis inhibitor TNP-470 on fibroproliferation of bleomycin-treated mouse lung. The contineous subcutaneal injection of All type 1 receptor antagonist (losartan, 20 mg/kg/day) reduced the hydroxyproline content (p=0.0140)in the lungs. The subcutaneal administration of TNP-470 (30 mg/kg), however, increased the contents of hydroxyproline (p=0.0092). These results suggested the tortuous involvement of angiogenesis in the early pathogenesis of pulmonary fibrosis.