Dual oxidase regulates neutrophil recruitment in allergic airways.
Dual oxidase regulates neutrophil recruitment in allergic airways.
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DOI：
10.1016/j.freeradbiomed.2013.06.012
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发表时间：
2013-12
影响因子：
7.4
通讯作者：
Harper, Richart
中科院分区：
文献类型：
--
作者：
Chang, Sandra;Linderholm, Angela;Franzi, Lisa;Kenyon, Nicholas;Grasberger, Helmut;Harper, Richart
过敏性气道中活性氧产生的增强已得到充分描述，并且与气道收缩增加、炎症细胞浸润、杯状细胞化生和粘液分泌过多相关。还有大量的白细胞介素 4/白细胞介素 13 (IL-4/IL-13) 或白细胞介素 5 分泌细胞被认为是过敏性哮喘发病机制的核心。我们假设双氧化酶（DUOX1 和 DUOX2）是烟酰胺腺嘌呤二核苷酸磷酸氧化酶家族的成员，可在呼吸道中释放过氧化氢（H2O2），是过敏性气道发病机制中的关键蛋白质。 DUOX 活性受 IL-4 和 IL-13 等细胞因子调节，DUOX 介导的 H2O2 影响过敏性哮喘的几个重要特征：粘蛋白产生、IL-8 分泌和伤口愈合。本研究的目的是在小鼠模型中确定 DUOX 对过敏性哮喘发展的贡献。为了实现这一目标，我们利用了 DUOXA 缺陷型小鼠模型 (Duoxa−/−)，该模型缺乏 DUOX1 和 DUOX2 的成熟因子。我们的结果首次证明了小鼠气道上皮中 DUOX 蛋白和 DUOX 功能活性的证据。我们还证明，DUOXA 成熟因子是气道特异性 H2O2 产生和 DUOX 定位到完全分化的气道上皮细胞纤毛所必需的。我们在卵清蛋白暴露模型中比较了野生型和 Duoxa−/− 小鼠，以确定 DUOX 在过敏性哮喘中的作用。与 DUOX 完整小鼠相比，Duoxa−/− 小鼠的粘液细胞化生减少，支气管肺泡液中 TH2 细胞因子水平较低。此外，正如预期的那样，在 Duoxa+/+ 小鼠中观察到响应乙酰甲胆碱而增加的气道阻力，但在 Duoxa−/− 小鼠中却没有观察到。令人惊讶的是，Duoxa−/− 小鼠支气管肺泡液和肺组织切片中中性粒细胞的流入减少，这与趋化细胞因子白细胞介素 6 的水平较低有关。这些发现表明，DUOX 衍生的 H2O2 在向中性粒细胞发出信号进入过敏性气道方面具有重要作用。
Enhanced reactive oxygen species production in allergic airways is well described, and correlates with increased airway contractions, inflammatory cell infiltration, goblet cell metaplasia, and mucus hypersecretion. There is also an abundance of interleukin-4/interleukin-13 (IL-4/IL-13) or interleukin-5-secreting cells that are thought to be central to the pathogenesis of allergic asthma. We postulated that dual oxidases (DUOX1 and DUOX2), members of the nicotinamide adenine dinucleotide phosphate oxidase family that release hydrogen peroxide (H2O2) in the respiratory tract, are critical proteins in the pathogenesis of allergic airways. DUOX activity is regulated by cytokines including IL-4 and IL-13, and DUOX-mediated H2O2 influences several important features of allergic asthma: mucin production, IL-8 secretion, and wound healing. The objective of this study was to establish the contribution of DUOX to the development of allergic asthma in a murine model. To accomplish this goal, we utilized a DUOXA-deficient mouse model (Duoxa−/−) that lacked maturation factors for both DUOX1 and DUOX2. Our results are the first to demonstrate evidence of DUOX protein and DUOX functional activity in murine airway epithelium. We also demonstrate that DUOXA maturation factors are required for airway-specific H2O2 production and localization of DUOX to cilia of fully differentiated airway epithelial cells. We compared wild-type and Duoxa−/− mice in an ovalbumin exposure model to determine the role of DUOX in allergic asthma. In comparison to DUOX-intact mice, Duoxa−/− mice had reduced mucous cell metaplasia, and lower levels of TH2 cytokine levels in bronchoalveolar fluid. In addition, increased airway resistance in response to methacholine was observed in Duoxa+/+ mice as expected, but was absent in Duoxa−/− mice. Surprisingly, Duoxa−/− mice had decreased influx of neutrophils in bronchoalveolar fluid and lung tissue sections associated with a lower level of the chemotactic cytokine interleukin-6. These findings suggest that DUOX-derived H2O2 has an important role in signaling neutrophils into allergic airways.
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影响因子：
4.8
作者：
Grasberger, Helmut;Refetoff, Samuel
通讯作者：
Refetoff, Samuel
影响因子：
5
作者：
Kenyon, Nicholas J.;Liu, Ruiwu;Lam, Kit S.
通讯作者：
Lam, Kit S.
影响因子：
3.8
作者：
Kenyon, Nicholas J.;Bratt, Jennifer M.;Last, Jerold A.
通讯作者：
Last, Jerold A.
DOI：
10.1152/ajplung.00025.2008
发表时间：
2008-06-01
影响因子：
4.9
作者：
Koff, Jonathan L.;Shao, Matt X. G.;Nadel, Jay A.
通讯作者：
Nadel, Jay A.
影响因子：
7.3
作者：
Kwon J;Shatynski KE;Chen H;Morand S;de Deken X;Miot F;Leto TL;Williams MS
通讯作者：
Williams MS