The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis.
The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis.
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DOI：
10.1186/1465-9921-6-11
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发表时间：
2005-01-21
影响因子：
5.8
通讯作者：
Lagente V
中科院分区：
文献类型：
--
作者：
Manoury B;Nenan S;Leclerc O;Guenon I;Boichot E;Planquois JM;Bertrand CP;Lagente V
活性氧和组织重塑调节因子，如金属蛋白酶（MMPs）及其抑制剂（TIMPs），被认为参与肺纤维化的发展。我们研究了这些因素在p47phox -/- (KO)小鼠对博莱霉素的纤维化反应中，这些小鼠缺乏通过nadph氧化酶途径产生ROS。小鼠通过鼻内滴注0.1 mg博来霉素。麻醉小鼠24 h或14 d后，分别进行支气管肺泡灌洗（BAL）或肺切除。博来霉素处理的WT小鼠BAL细胞在PMA刺激后ROS生成增强，而p47phox -/-小鼠BAL细胞未见变化。在第1天，博莱霉素诱导的急性炎症反应（BAL液中中性粒细胞计数和MMP-9活性增加）在KO中显著高于野生型（WT）小鼠，而IL-6水平在后者中显著增加。博来霉素给药后14天肺组织羟脯氨酸检测显示，KO小鼠肺组织中没有胶原沉积，羟基脯氨酸水平明显低于WT小鼠。WT小鼠给予博来霉素后第1天MMP-9/TIMP-1比值无变化，而KO小鼠则显著升高。到第14天，两种菌株的比例均较基线显著下降，但WT菌株的比例高于KO菌株。这些结果表明，nadph氧化酶衍生的ROS对肺纤维化的发展至关重要。KO小鼠中胶原沉积的缺失似乎与肺部MMP-9/TIMP-1比值升高有关。这一发现强调了金属蛋白酶和蛋白酶/抗蛋白酶失衡在肺纤维化中的重要性。
Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47phox -/- (KO) mice, deficient for ROS production through the NADPH-oxidase pathway. Mice are administered by intranasal instillation of 0.1 mg bleomycin. Either 24 h or 14 days after, mice were anesthetized and underwent either bronchoalveolar lavage (BAL) or lung removal. BAL cells from bleomycin treated WT mice showed enhanced ROS production after PMA stimulation, whereas no change was observed with BAL cells from p47phox -/- mice. At day 1, the bleomycin-induced acute inflammatory response (increased neutrophil count and MMP-9 activity in the BAL fluid) was strikingly greater in KO than wild-type (WT) mice, while IL-6 levels increased significantly more in the latter. Hydroxyproline assays in the lung tissue 14 days after bleomycin administration revealed the absence of collagen deposition in the lungs of the KO mice, which had significantly lower hydroxyproline levels than the WT mice. The MMP-9/TIMP-1 ratio did not change at day 1 after bleomycin administration in WT mice, but increased significantly in the KO mice. By day 14, the ratio fell significantly from baseline in both strains, but more in the WT than KO strains. These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis.
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DOI：
10.1164/ajrccm.162.5.9906096
发表时间：
2000-11-01
影响因子：
24.7
作者：
Suga, M;Iyonaga, K;Ando, M
通讯作者：
Ando, M
影响因子：
7.3
作者：
Serrano-Mollar, A;Closa, D;Bulbena, O
通讯作者：
Bulbena, O
DOI：
10.1165/ajrcmb.27.2.4674
发表时间：
2002-08-01
影响因子：
6.4
作者：
Kolb, M;Bonniaud, P;Gauldie, J
通讯作者：
Gauldie, J
影响因子：
9.6
作者：
Dunsmore, SE;Roes, J;Laurent, GJ
通讯作者：
Laurent, GJ
影响因子：
5.1
作者：
GALLIN, JI;BUESCHER, ES
通讯作者：
BUESCHER, ES