Alveolar Macrophages Stimulate Enhanced Cytokine Production by Pulmonary CD4+ T-Lymphocytes in an Exacerbation of Murine Chronic Asthma
Alveolar Macrophages Stimulate Enhanced Cytokine Production by Pulmonary CD4+ T-Lymphocytes in an Exacerbation of Murine Chronic Asthma
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DOI：
10.2353/ajpath.2010.100019
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发表时间：
2010-10-01
影响因子：
6
通讯作者：
Kumar, Rakesh K.
中科院分区：
文献类型：
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作者：
Herbert, Cristan;Scott, Melissa M.;Kumar, Rakesh K.
以哮喘急性加重为特征的远端呼吸道炎症和高反应性夸大的潜在机制在很大程度上是未知的。利用BALB/c小鼠实验模型，我们证明了肺泡巨噬细胞(AM)在过敏原诱导的哮喘恶化过程中具有潜在的重要作用。为了诱导轻度慢性哮喘的呼吸道炎症和重塑特征，对动物进行系统致敏，并将其暴露于低质量浓度(约3 mg/m(3))的雾化卵清蛋白中，每天30分钟，每周3天，共4周。随后的一次中等水平的激发(大约30 mg/m(3))被用来触发急性加重。在慢性激发的动物中，AM的细胞因子表达没有增加，而在急性发作后，AM表现出明显的促炎细胞因子的表达，包括IL-1β、IL-6、CXCL-1和肿瘤坏死因子a。同时，CD_4(+)T细胞表达多种细胞因子，尤其是Th2细胞因子IL-4和IL-13。重要的是，来自急性加重的AM在与来自慢性挑战的动物的CD4(+)细胞共同培养时刺激Th2细胞因子的表达，并且他们这样做的能力显著高于来自慢性挑战或幼稚对照的AM。刺激部分依赖于涉及CD80/86的相互作用。我们的结论是，在哮喘急性加重期，AM增强的细胞因子表达可能在触发肺内CD4(+)T淋巴细胞细胞因子表达增加中起关键作用。(Am J Pathol2010,177：1657-1664；DOI：10.2353/ajpath.2010.100019)
The mechanisms underlying the exaggerated distal airway inflammation and hyperresponsiveness that characterize acute exacerbations of asthma are largely unknown. Using BALB/c mouse experimental models, we demonstrated a potentially important role for alveolar macrophages (AM) in the development of an allergen-induced exacerbation of asthma. To induce features of airway inflammation and remodeling characteristic of mild chronic asthma, animals were systemically sensitized and exposed to low mass concentrations (approximate to 3 mg/m(3)) of aerosolized ovalbumin for 30 minutes per day, 3 days per week, for 4 weeks. A subsequent single moderate-level challenge (approximate to 30 mg/m(3)) was used to trigger an acute exacerbation. In chronically challenged animals, cytokine expression by AM was not increased, whereas after an acute exacerbation, AM exhibited significantly enhanced expression of proinflammatory cytokines, including interleukin (IL) 1 beta, IL-6, CXCL-1, and tumor necrosis factor a. In parallel, there was a marked increase in the expression of several cytokines by CD4(+) T-lymphocytes, notably the Th2 cytokines IL-4 and IL-13. Importantly, AM from an acute exacerbation stimulated the expression of Th2 cytokines when cocultured with CD4(+) cells from chronically challenged animals, and their ability to do so was significantly greater than AM from either chronically challenged or naive controls. Stimulation was partly dependent on interactions involving CD80/86. We conclude that in an acute exacerbation of asthma, enhanced cytokine expression by AM may play a critical role in triggering increased expression of cytokines by pulmonary CD4(+) T-lymphocytes. (Am J Pathol 2010, 177:1657-1664; DOI: 10.2353/ajpath.2010.100019)