Pivotal role of matrix metalloproteinase 13 in extracellular matrix turnover in idiopathic pulmonary fibrosis.
Pivotal role of matrix metalloproteinase 13 in extracellular matrix turnover in idiopathic pulmonary fibrosis.
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DOI：
10.1371/journal.pone.0073279
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Günther A
中科院分区：
文献类型：
--
作者：
Nkyimbeng T;Ruppert C;Shiomi T;Dahal B;Lang G;Seeger W;Okada Y;D'Armiento J;Günther A
特发性肺纤维化(IPF)是一种以细胞外基质(ECM)过度沉积为特征的致死性疾病。我们研究了基质金属蛋白酶(MMPs)及其抑制物(TIMPs)在肺纤维化中的调节作用。比较IPF(n=16)和供体(n=6)肺组织匀浆中基质金属蛋白酶(MMPs)和组织金属蛋白酶抑制剂(TIMP)的表达、胶原酶活性和胶原含量，并通过原位酶谱检测明胶蛋白和胶原酶活性，结合基质金属蛋白酶抗原检测。采用博莱霉素肺纤维化模型对MMP13-/-与野生型小鼠的作用进行了评估。在IPF中，MMPs-1、2、7、9和13显著上调，而MMP8无明显上调，而TIMP(1-4)无明显改变。胶原蛋白含量略有增加，胶原酶活性在呼吸道最为明显，并与基质金属蛋白酶-13共定位。我们观察到，与野生型小鼠相比，博莱霉素组与野生型小鼠相比，早期炎症反应加重，肺纤维化加重，在博莱霉素组小鼠28天后，肺胶原蛋白含量升高。我们的数据提示：i)IPF肺内胶原沉积不是由于TIMP的过度产生，而是由于面对整体但空间不平衡的胶原酶活性增加而产生的大量ECM；ii)胶原酶活性在呼吸道内的优先分布，主要是MMP-13，为蜂窝囊的发展提供了解释；iii)尽管炎症细胞含量总体增加，但MMP-13的存在似乎限制了ECM在肺纤维化中的沉积。
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by excessive deposition of extracellular matrix (ECM). We investigated the regulation of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lung fibrosis. MMP and TIMP expression, collagenolytic activity and collagen content was assessed in IPF (n=16) versus donor (n=6) lung homogenates and accomplished by in-situ-zymography for gelatinolytic and collagenolytic activities, combined with MMP antigen detection. Role of MMP13 was assessed employing the bleomycin model of lung fibrosis in MMP-13-/- versus wild-type mice. In IPF, MMPs-1, 2, 7, 9 and 13, but not MMP-8, were significantly upregulated, whereas none of the TIMPs (1–4) were significantly altered. Collagen content was slightly increased and collagenolytic activity was most prominent in the airways and co-localized with MMP-13. We observed an exaggerated early inflammatory response and an augmented lung fibrosis in bleomycin-challenged MMP-13-/- versus wild-type mice, with elevated lung collagen content 28d after bleomycin challenge in the MMP-13-/- mice. Our data suggest that i) collagen deposition in IPF lungs is not primarily due to excessive TIMP production, but rather due to overwhelming ECM production in face of an overall increased, but spatially imbalanced collagenolytic activity, ii) preferential distribution of collagenolytic activity, largely MMP-13, in the airways offers an explanation for the development of honeycomb cysts and iii) despite an overall increase in inflammatory cell content the presence of MMP-13 seems to limit the overall extent of ECM deposition in lung fibrosis.
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影响因子：
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作者：
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影响因子：
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发表时间：
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期刊：
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DOI：
10.1164/ajrccm.163.1.2002123
发表时间：
2001-01-01
影响因子：
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