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

为了澄清特发性肺纤维化（IPF）肺血管重构的明显矛盾，我们评估了7例IPF患者肺肺泡间隔内的血管密度（VD）与不同程度肺泡纤维化的关系，评分从1到8。CD34是肺泡毛细血管内皮细胞的良好标记，而VD（以毛细血管面积与肺泡壁总面积的相对比例确定）在低级别纤维化肺（评分1和2,23.4±1.17%）明显高于对照组（12.3±1.62%,p<0.0001）。血管化肺泡壁上的肺泡上皮细胞大量产生VEGF和IL-8，血管紧张素转换酶（ACE）在这些增加的毛细血管内皮细胞中表达增强。相反，随着纤维化程度的增加，VD逐渐降低，在最广泛的纤维病变中VD低于对照肺（评分7和8,5.10±0.54%,p=0.0003）。这些结果表明，肺泡毛细血管仅在IPF肺的早期病变中增加，这可能通过产生增加的ACE水平来促进纤维增殖。此外，我们在本研究中评估了(1)血管紧张素II （AII）的作用，血管紧张素转换酶在增加的毛细血管内皮细胞中表达增强，(2)血管生成抑制剂TNP-470对博莱霉素处理小鼠肺纤维增殖的影响。连续皮下注射All 1型受体拮抗剂（氯沙坦，20 mg/kg/天）可降低肺中羟脯氨酸含量（p=0.0140）。皮下注射TNP-470 （30 mg/kg）可使羟脯氨酸含量增加（p=0.0092）。这些结果提示在肺纤维化的早期发病机制中血管生成的曲折参与。

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.