Pulmonary structural remodeling and the role metalloproteinases in bleomycin-induced pulmonary fibrosis.

肺结构重塑和金属蛋白酶在博来霉素诱导的肺纤维化中的作用。

基本信息

批准号：
09670632
负责人：
FUKUDA Yuh
金额：
$ 1.86万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670632/
关键词：
pulmonary fibrosis bleomycin regenerating epithelial cells MMP MT-MMP TIMP gelatin zymography BAL ブレオマイシン線維芽細胞 IV-型コラーゲン

项目摘要

In pulmonary fibrosis, there are idiopathic pulmonary fibrosis which shows irreversible fibrosis and poor prognosis, and others which show reversible fibrosis and good prognosis. In this study, we investigated the role of metalloproteinases (MMP) which is important enzyme in the metabolism of extracellular matrices in bleomycin-induced pulmonary fibrosis in rabbit which is known to be reversible model. In the early stage, intraalveolar fibrosis was made, these fibrosis adhere to the alveolar walls and obliterate the alveolar spaces, and the alveolar structures were remodeled. These fibrosis was covered by the regenerated bronchiolar and alveolar epithelial cells. In later stage, fibrotic area was decreased in size and alveolar structures were reconstructed in association with the regeneration of alveolar epithelial cells. Immunohistochemical study revealed that MMP-l, MMP-2, MMP-9 and their inhibitor (TIMP)-2 were mainly localized in the regenerating epithelial cells. In addition to that, membrane type (MT-i) MMP which is known to be only one factor to activate MMP-2 in vivo was detected in the regenerating epithelial cells. Gelatin zymography of lung tissue homogenates showed significant increases of MMP-2 land the ratio of active formlinactive form MMP-2 in later stage of this model. Bronchoalveolar lavage fluid (BALF) also showed the significant increases of MMP-2 and the ratio of active formfinactive form MMP-2 in the later stage. It was suggested that MT-i MMP produced by the regenerating epithelial cells participates the activation of MMP-2 in vivo. We consider that the significant increase of the ratio of active form/inactive form MMP 2 in the fibrotic lesions may facilitate the process of the repair in the fibrotic lungs. It is also suggested that the possibility of the application of the gelatin zymography in BALF of the patients with pulmonary fibrosis.

肺纤维化有不可逆性纤维化、预后不良的特发性肺纤维化，以及可逆性纤维化、预后良好的特发性肺纤维化。在这项研究中，我们研究了金属蛋白酶（MMP）的作用，金属蛋白酶是细胞外基质代谢中的重要酶，在博莱霉素诱导的兔肺纤维化（已知是可逆模型）中的作用。早期形成肺泡内纤维化，这些纤维化附着在肺泡壁上并消灭肺泡腔，肺泡结构发生重塑。这些纤维化被再生的细支气管和肺泡上皮细胞覆盖。后期，纤维化面积缩小，肺泡结构重建，肺泡上皮细胞再生。免疫组化研究显示MMP-1、MMP-2、MMP-9及其抑制剂(TIMP)-2主要定位于再生上皮细胞。除此之外，在再生上皮细胞中检测到膜型(MT-i)MMP，其是已知的唯一体内激活MMP-2的因子。肺组织匀浆的明胶酶谱显示，在该模型的后期，MMP-2 和活性形式 MMP-2 的比例显着增加。支气管肺泡灌洗液(BALF)也显示后期MMP-2和活性形式MMP-2的比例显着增加。提示再生上皮细胞产生的MT-i MMP参与了体内MMP-2的激活。我们认为纤维化病灶中活性型/非活性型MMP 2 比例的显着增加可能有利于纤维化肺的修复过程。也提示明胶酶谱技术在肺纤维化患者BALF中应用的可能性。