Alterations In Pulmonary Immune Function And Host Resistance In COX Null Mice

COX 无效小鼠肺免疫功能和宿主抵抗力的变化

基本信息

项目摘要

We are investigating the role of cyclooxygenases in basal lung function and in the pulmonary response to environmental agents. At baseline, lung prostaglandin E2 levels are lower in COX-1 null mice compared to either wild type or COX-2 null mice, but there are no significant differences in basal lung function or in lung histopathology between the genotypes. Following allergen (ovalbumin) sensitizationexposure, lung inflammatory indices are significantly greater in COX-1 null and COX-2 null mice compared to wild type mice. Airways of allergic COX-1 null mice have increased numbers of eosinophils and increased numbers of CD3CD4 lymphocytes (Th cells). Alveolar macrophages from allergic COX-1 null airways show biochemical and morphologic evidence of activation. Bronchoalveolar lavage fluid (BALF) from allergic COX-1 null mice contains significantly higher levels of the Th2 cytokines IL-4, IL-5 and IL-13, increased levels of LTB4 and the cysteinyl leukotrienes, and increased levels of the chemokines TARC and eotaxin. These changes in the COX-1 null mice are associated with increased BALF IgE levels and increased MUC5AC productionmucin secretion. Moreover, expression of the adhesion molecules VCAM-1 and ICAM-1 are increased in the lungs of both allergic COX-1 and allergic COX-2 null mice. Allergic COX-1 null mice have reduced lung compliance, increased allergen-induced bronchoconstriction and display hyperresponsiveness to inhaled methacholine. We have also examined the effects of disruption of COX genes on the pulmonary responses to other environmentally relevant agents including inhaled endotoxin (bacterial lipopolysaccharide, LPS), vanadium pentoxide, and influenza virus. Following LPS exposure, all mice exhibit increased bronchoconstriction and methacholine hyperresponsiveness; however, these changes are much more pronounced in both the COX-1 null and COX-2 null mice relative to wild type controls. Interestingly, there are no significant differences in BALF cells or lung histopathology between the genotypes following LPS exposure. Thus, the balance of COX-1 and COX-2 is important in regulating the physiologic but not the inflammatory responses to inhaled LPS. Following vanadium pentoxide (V2O5) exposure, COX-2 null mice, but not COX-1 null mice, have increased acute lung inflammation and develop more lung fibrosis (increased lung hydroxyproline and enhanced trichrome staining). We have also utilized a pulmonary influenza infectivity model to evaluate host resistance and to determine if there are defects in innate or adaptive immune responses to viral infection in COX-1 null and COX-2 null mice. Infection induced less severe illness in COX-2 null mice in comparison to wild type and COX-1 null mice as evidenced by body weight and body temperature changes. Mortality was significantly reduced in COX-2 null mice. COX-1 null mice had enhanced inflammation and earlier appearance of pro-inflammatory cytokines in the BAL fluid, whereas the inflammatory and cytokine responses were blunted in COX-2 null mice. However, lung viral titres were markedly elevated in COX-2 null mice relative to wild type and COX-1 null mice. Levels of prostaglandin E2 were reduced in COX-1 null airways whereas cysteinyl leukotrienes were elevated in COX-2 null airways following infection. Thus, deficiency of COX-1 and COX-2 leads to contrasting effects in the host response to influenza infection, and these differences are associated with altered production of prostaglandins and leukotrienes following infection. The response of COX-deficient mice varies depending on the environmental stimulus. More recently, we developed transgenic mice with lung-specific overexpression of human COX-1 (murine CC10 promoter driven). Whereas no differences in basal respiratory or lung mechanical parameters were observed, COX-1 transgenic mice had increased bronchoalveolar lavage fluid prostaglandin E2 content compared to wild type littermates and exhibited decreased airway responsiveness to inhaled methacholine. In an ovalbumin-induced allergic airway inflammation model, comparable upregulation of COX-2 protein was observed in the lungs of allergic wild-type and COX 1 transgenic mice. Furthermore, no genotype differences were observed in allergic mice in total cell number, eosinophil content and inflammatory cytokine content of bronchoalveolar lavage fluid, or in airway responsiveness to inhaled methacholine. To eliminate the presumed confounding effects of COX-2 upregulation, COX-1 transgenic mice were bred into a COX-2 null background. In these mice, 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. We are currently developing transgenic mice with overexpression of COX-2 in type II cells (SPA promoter driven) to examine the role of COX-2 in the distal airway. We are also developing mice with selective knockout of COX-2 in the lung (Clara cells, type II alveolar cells) to determine if systemic or local biosynthesis of prostaglandins is important in regulating the lung response to environmental agents. Finally, we are studying the role of COX-1 and COX-2 in differentiation of lung T-cells in vitro and in vivo.
我们正在研究环氧化酶在基础肺功能和肺对环境因子的反应中的作用。基线时,考克斯-1基因敲除小鼠的肺前列腺素E2水平低于野生型或考克斯-2基因敲除小鼠,但基因型之间的基础肺功能或肺组织病理学无显著差异。在过敏原(卵清蛋白)致敏暴露后,考克斯-1和考克斯-2缺失小鼠的肺部炎症指数明显高于野生型小鼠。过敏性考克斯-1基因敲除小鼠气道嗜酸性粒细胞数量增加,CD 3 CD 4淋巴细胞(Th细胞)数量增加。过敏性考克斯-1缺失气道的肺泡巨噬细胞显示出活化的生化和形态学证据。过敏性考克斯-1缺失小鼠的支气管肺泡灌洗液(BALF)含有显着较高水平的Th 2细胞因子IL-4、IL-5和IL-13,LTB 4和半胱氨酰白三烯水平升高,以及趋化因子TARC和嗜酸性粒细胞趋化因子水平升高。考克斯-1基因敲除小鼠的这些变化与BALF IgE水平升高和MUC 5AC产生增加有关。此外,在过敏性考克斯-1和过敏性考克斯-2缺失小鼠的肺中粘附分子VCAM-1和ICAM-1的表达增加。过敏性考克斯-1基因敲除小鼠肺顺应性降低,过敏原诱导的支气管收缩增加,并对吸入乙酰甲胆碱表现出高反应性。我们还研究了考克斯基因的破坏对肺对其他环境相关因子的反应的影响,这些环境相关因子包括吸入性内毒素(细菌脂多糖,LPS)、五氧化二钒和流感病毒。LPS暴露后,所有小鼠均表现出增加的支气管收缩和乙酰甲胆碱高反应性;然而,相对于野生型对照,这些变化在考克斯-1缺失和考克斯-2缺失小鼠中更为明显。有趣的是,在LPS暴露后,基因型之间的BALF细胞或肺组织病理学没有显著差异。因此,考克斯-1和考克斯-2的平衡在调节对吸入LPS的生理反应而不是炎症反应中是重要的。在五氧化二钒(V2 O 5)暴露后,考克斯-2缺失小鼠,而不是考克斯-1缺失小鼠,具有增加的急性肺部炎症和发展更多的肺纤维化(增加的肺羟脯氨酸和增强的三色染色)。我们还利用肺流感传染性模型来评估宿主抗性,并确定考克斯-1无效和考克斯-2无效小鼠中对病毒感染的先天性或适应性免疫应答是否存在缺陷。与野生型和考克斯-1缺失小鼠相比,感染在考克斯-2缺失小鼠中诱导较不严重的疾病,如体重和体温变化所证明的。 死亡率在考克斯-2缺失小鼠中显著降低。 考克斯-1基因敲除小鼠的炎症反应增强,并且在BAL液中较早出现促炎细胞因子,而考克斯-2基因敲除小鼠的炎症反应和细胞因子反应减弱。 然而,相对于野生型和考克斯-1缺失小鼠,考克斯-2缺失小鼠的肺病毒滴度显著升高。 前列腺素E2水平在考克斯-1无效气道中降低,而半胱氨酰白三烯在感染后考克斯-2无效气道中升高。 因此,考克斯-1和考克斯-2的缺乏导致宿主对流感感染的反应中的对比效应,并且这些差异与感染后异莲心素和白三烯的产生改变有关。 COX缺陷小鼠的反应取决于环境刺激。 最近,我们开发了肺特异性过表达人考克斯-1(鼠CC 10启动子驱动)的转基因小鼠。尽管未观察到基础呼吸或肺机械参数的差异,但与野生型同窝小鼠相比,考克斯-1转基因小鼠的支气管肺泡灌洗液前列腺素E2含量增加,并表现出对吸入乙酰甲胆碱的气道反应性降低。 在卵白蛋白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转基因小鼠的肺中观察到考克斯-2蛋白的相当的上调。 此外,没有基因型差异,观察过敏小鼠的总细胞数,嗜酸性粒细胞含量和炎症细胞因子含量的支气管肺泡灌洗液,或在气道反应性吸入乙酰甲胆碱。 为了消除推测的考克斯-2上调的混杂效应,将考克斯-1转基因小鼠饲养到考克斯-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。我们目前正在开发II型细胞中过表达考克斯-2的转基因小鼠(SPA启动子驱动),以研究考克斯-2在远端气道中的作用。 我们也正在开发选择性敲除肺(Clara细胞,II型肺泡细胞)中考克斯-2的小鼠,以确定在调节肺对环境因子的反应中,木菠萝素的全身或局部生物合成是否重要。最后,我们正在研究考克斯-1和考克斯-2在体外和体内肺T细胞分化中的作用。

项目成果

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Darryl C Zeldin其他文献

Darryl C Zeldin的其他文献

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{{ truncateString('Darryl C Zeldin', 18)}}的其他基金

Eicosanoids and Lung Function
类二十烷酸和肺功能
  • 批准号:
    6106636
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
CARDIAC CYTOCHROME P450 ARACHIDONIC ACID EPOXYGENASE PATHWAY
心脏细胞色素 P450 花生四烯酸环氧化酶途径
  • 批准号:
    6289939
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
EICOSANOIDS AND LUNG FUNCTION
类花生酸和肺功能
  • 批准号:
    6289940
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
Arachidonic acid metabolism by murine CYP2C isoforms
小鼠 CYP2C 亚型对花生四烯酸的代谢
  • 批准号:
    6413417
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
Characterization And Functional Significance Of P450 Ara
P450 Ara 的表征及功能意义
  • 批准号:
    7168262
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
Indoor Allergens And Asthma
室内过敏原和哮喘
  • 批准号:
    7168263
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
Alterations In Pulmonary Immune Function And Host Resist
肺免疫功能和宿主抵抗力的改变
  • 批准号:
    7168264
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
Role of Estrogen Receptors in Lung Function
雌激素受体在肺功能中的作用
  • 批准号:
    8336630
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
Program in Clinical Research, Clinical Support Services and Clinical Training
临床研究、临床支持服务和临床培训项目
  • 批准号:
    7734571
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:
Characterization And Functional Significance Of P450 Arachidonate Epoxygenases
P450 花生四烯酸环氧合酶的特征和功能意义
  • 批准号:
    10919036
  • 财政年份:
  • 资助金额:
    $ 57.44万
  • 项目类别:

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环境过敏原影响过敏性炎症细胞的功能
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II免疫耐受网络:空气中的过敏原和过敏性鼻炎
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II免疫耐受网络:空气中的过敏原和过敏性鼻炎
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