Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases.
Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases.
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发表时间：
1998-06
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通讯作者：
Y. Fukuda;M. Ishizaki;S. Kudoh;M. Kitaichi;Nobuaki Yamanaka
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作者：
Y. Fukuda;M. Ishizaki;S. Kudoh;M. Kitaichi;Nobuaki Yamanaka
在间质性肺疾病中，肺泡内细胞外基质(ECM)沉积和降解导致肺结构重建。观察了闭塞性毛细支气管炎机化性肺炎(BOOP)和特发性肺纤维化(IPF)患者肺组织细胞外基质(ECM)的变化及基质金属蛋白酶(MMPs)及其组织抑制物(TIMP)的分布。免疫组织化学方法检测纤维连接蛋白、I、III、IV型胶原、平滑肌肌动蛋白、间质胶原酶、明胶酶A、明胶酶B、明胶酶2的表达，原位杂交检测基质金属蛋白酶9mRNA的表达。采用免疫印迹法检测肺组织匀浆中MMP2和MMP9的表达。用明胶酶谱法测定了各匀浆的明胶分解活性。纤维连接蛋白和I型、III型、IV型胶原在肺泡内纤维化及间质中均有表达。基质金属蛋白酶-1、基质金属蛋白酶-2、基质金属蛋白酶-9和基质金属蛋白酶-2在肺泡内纤维化的再生上皮细胞中表达。BOOP肺泡内纤维化的肌成纤维细胞主要表达MMPs，其超微结构表现为吞噬胶原纤维，IPF中主要表达TIMP-2。肺泡内纤维化中的新生血管仅在BOOP病例中观察到，内皮细胞基质金属蛋白酶-2阳性。免疫印迹显示肺组织中存在潜伏型和潜伏型及活性两种形态的基质金属蛋白酶-2，明胶酶谱显示肺组织中基质金属蛋白酶-2的活性/潜伏型比值明显高于对照组。BOOP中主要的MMPs可能构成了本病纤维化改变的可逆性机制。TIMP-2在IPF中的表达可能参与了细胞外基质的稳定沉积和不可逆转的肺结构重建。
In interstitial lung diseases, deposition of extracellular matrix (ECM) in alveoli and degradation of ECM lead to pulmonary structural remodeling. The changes in ECM and the localization of matrix metalloproteinases (MMPs) and a tissue inhibitor of metalloproteinases (TIMP) in the lung tissues of patients with bronchiolitis obliterans organizing pneumonia (BOOP) and idiopathic pulmonary fibrosis (IPF) were investigated. Immunohistochemical analysis for the detection of fibronectin, collagen-I, -III, and -IV, smooth muscle actin, MMP-1 (interstitial collagenase), -2 (gelatinase A), and -9 (gelatinase B), and TIMP-2, and in situ hybridization for the detection of MMP-9 mRNA were performed. Western blotting of lung tissue homogenates was performed for MMP-2 and MMP-9. The gelatinolytic activities of the homogenates were also determined using gelatin zymography. Fibronectin and collagen-I, -III, and -IV were detected in the intra-alveolar fibrosis in addition to the interstitium of these diseases. MMP-1, MMP-2, MMP-9, and TIMP-2 were detected in the regenerated epithelial cells covering intra-alveolar fibrosis. Myofibroblasts in intra-alveolar fibrosis in BOOP showed predominant reaction for MMPs, and they ultrastructurally appeared to be phagocytosing collagen fibrils, and those of IPF showed a predominant reaction for TIMP-2. New vascularization in intra-alveolar fibrosis was exclusively observed in cases of BOOP, and the endothelial cells were positive for MMP-2. Western blotting showed the existence of a latent form of MMP-9 and latent and active forms of MMP-2, and gelatin zymography revealed that the ratio of active/latent forms of MMP-2 in BOOP is significantly larger than that in the control lungs. Predominant MMPs in BOOP may constitute the mechanism of reversibility of fibrotic changes in this disease. TIMP-2 in myofibroblasts in IPF may contribute to the stable ECM deposition and the irreversible pulmonary structural remodeling.