Cyclooxygenase-1 overexpression decreases basal airway responsiveness but not allergic inflammation
Cyclooxygenase-1 overexpression decreases basal airway responsiveness but not allergic inflammation
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DOI：
10.4049/jimmunol.177.7.4785
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发表时间：
2006-10-01
影响因子：
4.4
通讯作者：
Zeldin, Darryl C.
中科院分区：
文献类型：
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作者：
Card, Jeffrey W.;Carey, Michelle A.;Zeldin, Darryl C.
环氧化酶（考克斯）-1或考克斯-2的药理学抑制或遗传破坏加剧了肺对环境相关刺激的炎症和功能反应。为了进一步检查COX衍生的类二十烷酸对基础肺功能和变应性肺部炎症的贡献，产生转基因（Tr）小鼠，其中人考克斯-1的过表达靶向气道上皮。尽管在基础呼吸或肺机械参数上没有观察到差异，但与野生型同窝小鼠相比，考克斯-1 Tr小鼠的支气管肺泡灌洗液中PGE（2）含量增加（23.0 +/- 3.6 vs 8.4 +/- 1.4 pg/ml; p < 0.05），并表现出对吸入乙酰甲胆碱的气道反应性降低。在OVA诱导的过敏性气道炎症模型中，在过敏性野生型和考克斯-1 Tr小鼠的肺中观察到相当的考克斯-2蛋白上调。此外，在过敏小鼠中，在总细胞数、嗜酸性粒细胞含量（分别占总细胞的70%和76%）、支气管肺泡灌洗液中的炎性细胞因子含量或气道对吸入乙酰甲胆碱的反应性方面没有观察到基因型差异（p > 0.05）。为了消除推测的考克斯-2上调的混杂效应，将考克斯-1 Tr小鼠饲养到考克斯-2无效背景中。在这些小鼠中，考克斯-1转基因的存在并没有改变过敏原诱导的炎症，但显着减弱过敏原诱导的气道高反应性，与降低气道白三烯水平一致。总的来说，这些数据表明，考克斯-1过表达减弱气道反应性在基础条件下，但不影响过敏性气道炎症。
Pharmacological inhibition or genetic disruption of cyclooxygenase (COX)-1 or COX-2 exacerbates the inflammatory and functional responses of the lung to environmentally relevant stimuli. To further examine the contribution of COX-derived eicosanoids to basal lung function and to allergic lung inflammation, transgenic (Tr) mice were generated in which overexpression of human COX-1 was targeted to airway epithelium. Although no differences in basal respiratory or lung mechanical parameters were observed, COX-1 Tr mice had increased bronchoalveolar lavage fluid PGE(2) content compared with wild-type littermates (23.0 +/- 3.6 vs 8.4 +/- 1.4 pg/ml; p < 0.05) and exhibited decreased airway responsiveness to inhaled methacholine. In an OVA-induced allergic airway inflammation model, comparable up-regulation of COX-2 protein was observed in the lungs of allergic wild-type and COX-1 Tr mice. Furthermore, no genotype differences were observed in allergic mice in total cell number, eosinophil content (70 vs 76% of total cells, respectively), and inflammatory cytokine content of bronchoalveolar lavage fluid, or in airway responsiveness to inhaled methacholine (p > 0.05). To eliminate the presumed confounding effects of COX-2 up-regulation, COX-1 Tr mice were bred into a COX-2 null background. In these mice, the presence of the COX-1 transgene did not alter allergen-induced inflammation but significantly attenuated allergen-induced airway hyperresponsiveness, coincident with reduced airway leukotriene levels. Collectively, these data indicate that COX-1 overexpression attenuates airway responsiveness under basal conditions but does not influence allergic airway inflammation.