Requirement for inducible nitric oxide synthase in chronic allergen exposure-induced pulmonary fibrosis but not inflammation.
Requirement for inducible nitric oxide synthase in chronic allergen exposure-induced pulmonary fibrosis but not inflammation.
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DOI：
10.4049/jimmunol.0904214
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发表时间：
2010-09-01
期刊：
影响因子：
--
通讯作者：
Boulares AH
中科院分区：
文献类型：
--
作者：
Naura AS;Zerfaoui M;Kim H;Abd Elmageed ZY;Rodriguez PC;Hans CP;Ju J;Errami Y;Park J;Ochoa AC;Boulares AH
诱导型一氧化氮合酶(INOS)在过敏性呼吸道炎症中的作用仍不清楚。我们验证了iNOS在急性和慢性呼吸道炎症中发挥不同作用的假设。采用卵清蛋白诱导的小鼠急性和慢性呼吸道炎症模型进行研究。我们发现iNOS缺失与急性方案中的嗜酸性粒细胞增多、粘液高分泌以及IL-5和IL-13的产生减少有关。这种保护在《长期议定书》中被完全废除。有趣的是，在慢性方案下观察到的野生型小鼠的肺纤维化在诱导型−/−小鼠中完全没有，尽管持续产生IL-5和IL-13，这表明这些细胞因子在肺纤维化中是不够的。这种保护与胶原合成减少和间接但严重的转化生长因子-β调节有关，这一点在原代肺平滑肌细胞中得到证实。虽然基质金属蛋白酶-2/-9的活性变化不大，但在野生型小鼠中检测到的金属蛋白酶组织抑制物-2(TIMP-2)的大量增加在诱导型一氧化氮合酶−/−对应的小鼠中是缺失的。诱导型一氧化氮合酶对TIMP-2的调节作用可能是通过过氧亚硝酸盐介导的，后者逆转了诱导型一氧化氮合酶−/−肺平滑肌细胞和成纤维细胞中TIMP-2的表达，提示诱导型一氧化氮合酶-TIMP-2环节可能解释了诱导型一氧化氮合酶基因敲除对肺纤维化的保护作用。对慢性卵清蛋白暴露的诱导型一氧化氮合酶−/−小鼠肺切片的分析显示，残留但显著的蛋白质硝化、普遍的氧化性DNA损伤和多聚(腺苷二磷酸-核糖)聚合酶-1激活。这种组织损伤、炎性细胞募集和粘液高分泌可能与大量精氨酸酶的表达和活性有关。这项研究的结果证明了诱导型一氧化氮合酶在哮喘中作用的复杂性，以及它作为治疗靶点的潜力的保存。
The role of inducible NO synthase (iNOS) in allergic airway inflammation remains elusive. We tested the hypothesis that iNOS plays different roles during acute versus chronic airway inflammation. Acute and chronic mouse models of OVA-induced airway inflammation were used to conduct the study. We showed that iNOS deletion was associated with a reduction in eosinophilia, mucus hypersecretion, and IL-5 and IL-13 production upon the acute protocol. Such protection was completely abolished upon the chronic protocol. Interestingly, pulmonary fibrosis observed in wild-type mice under the chronic protocol was completely absent in iNOS−/− mice despite persistent IL-5 and IL-13 production, suggesting that these cytokines were insufficient for pulmonary fibrosis. Such protection was associated with reduced collagen synthesis and indirect but severe TGF-β modulation as confirmed using primary lung smooth muscle cells. Although activation of matrix metalloproteinase-2/-9 exhibited little change, the large tissue inhibitor of metalloproteinase-2 (TIMP-2) increase detected in wild-type mice was absent in the iNOS−/− counterparts. The regulatory effect of iNOS on TIMP-2 may be mediated by peroxynitrite, as the latter reversed TIMP-2 expression in iNOS−/− lung smooth muscle cells and fibroblasts, suggesting that the iNOS–TIMP-2 link may explain the protective effect of iNOS-knockout against pulmonary fibrosis. Analysis of lung sections from chronically OVA-exposed iNOS−/− mice revealed evidence of residual but significant protein nitration, prevalent oxidative DNA damage, and poly(ADP-ribose) polymerase-1 activation. Such tissue damage, inflammatory cell recruitment, and mucus hypersecretion may be associated with substantial arginase expression and activity. The results in this study exemplify the complexity of the role of iNOS in asthma and the preservation of its potential as a therapeutic a target.
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影响因子：
3.7
作者：
Hans CP;Feng Y;Naura AS;Zerfaoui M;Rezk BM;Xia H;Kaye AD;Matrougui K;Lazartigues E;Boulares AH
通讯作者：
Boulares AH
影响因子：
14.2
作者：
Jain, VV;Kitagaki, K;Kline, JN
通讯作者：
Kline, JN
DOI：
10.1165/rcmb.2001-0015oc
发表时间：
2003-03-01
影响因子：
6.4
作者：
Boulares, AH;Zoltoski, AJ;Smulson, ME
通讯作者：
Smulson, ME
DOI：
10.1513/pats.200806-054rm
发表时间：
2009-05-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Janssen-Heininger, Yvonne M W;Poynter, Matthew E;van der Vliet, Albert
通讯作者：
van der Vliet, Albert
影响因子：
4.8
作者：
Boulares, AH;Yakovlev, AG;Smulson, M
通讯作者：
Smulson, M