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

特发性肺纤维化肺部肺泡毛细血管的重塑。

基本信息

批准号：
11670562
负责人：
EBINA Masahito
金额：
$ 2.18万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670562/
关键词：
Pulmonary fibrosis Angiogenesis Angiotensin Angiotensin-converthing enzyme bleomycin

项目摘要

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.

为了阐明特发性肺纤维化（IPF）肺血管重塑中的明显矛盾，我们评估了7例IPF患者肺中肺泡隔内的血管密度（VD）与不同程度的肺泡纤维化的关系，评分从1到8。CD 34是肺泡毛细血管内皮细胞的一个很好的标记物，而VD，即毛细血管面积与肺泡壁总面积的相对比值，在低级别纤维化组（1和2分，23.4±1.17%）显著高于对照组（12.3± 1.62%，p<0.0001）。VEGF和IL-8，强有力的血管生成因子，是非常产生的肺泡上皮细胞内衬血管化肺泡壁，血管紧张素转换酶（ACE）的表达增强，观察到在这些增加的毛细血管内皮细胞。相反，随着纤维化程度的增加，VD逐渐降低，并且在最广泛的纤维病变中低于对照肺的VD（评分7和8，5.10± 0.54%，p=0.0003）。这些结果表明，肺泡毛细血管的增加，只有在早期病变的肺IPF，这将有助于纤维增生，产生一个增加的ACE水平。此外，我们在这项研究中评估（1）血管紧张素II（AII）的作用，血管紧张素转换酶增加表达的毛细血管内皮细胞，（2）血管生成抑制剂TNP-470对博莱霉素处理的小鼠肺纤维化的影响。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）。然而，皮下给药TNP-470（30 mg/kg），增加羟脯氨酸的含量（p=0.0092）。这些结果表明，血管生成曲折参与肺纤维化的早期发病机制。