Alternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness.
Alternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness.
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DOI：
10.4049/jimmunol.1101632
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发表时间：
2012-03-15
期刊：
影响因子：
--
通讯作者：
Broide DH
中科院分区：
文献类型：
--
作者：
Doherty TA;Khorram N;Sugimoto K;Sheppard D;Rosenthal P;Cho JY;Pham A;Miller M;Croft M;Broide DH
真菌过敏原Alternaria与严重哮喘特别相关，包括危及生命的病情恶化。为了更好地了解交链孢属的急性先天呼吸道反应，对幼稚的WT小鼠进行了一次鼻腔内交链孢属攻击。24小时后分析，幼稚的WT小鼠在交链孢子虫攻击后出现显著的BAL嗜酸性粒细胞增多。与交链孢霉不同，曲霉和念珠菌均不能诱导BAL嗜酸性粒细胞增多。对呼吸道上皮细胞刷取的基因芯片分析表明，链格孢霉攻击的幼稚WT小鼠的抵抗素样分子“在炎症区1发现”(FIZZ1/Retnla)的表达水平增加了20倍以上。肺免疫染色证实，FIZZ1在单一交链孢菌攻击后3小时就有强烈的呼吸道上皮细胞表达，持续至少5天，在STAT6缺陷小鼠中显著减少，但不是PAR-2缺陷小鼠。骨髓嵌合体研究表明，上皮性FIZZ1的表达需要在肺细胞中表达STAT6，而骨髓来源的细胞中存在的STAT6参与了气道嗜酸性粒细胞增多症。研究表明，CD45+CD11c+(巨噬细胞和树突状细胞)以及产生CD45的CD45阴性细胞(成纤维细胞)可以与FIZZ1结合。重要的是，直接给幼稚的WT小鼠注射重组FIZZ1会导致气道嗜酸性粒细胞增多、支气管周围纤维化和呼吸道上皮厚度增加。因此，链格孢霉诱导STAT-6依赖的急性呼吸道嗜酸性粒细胞和上皮FIZZ1的表达，从而促进气道纤维化和上皮厚度。这可能对链格孢菌相关性哮喘的独特致病方面提供一些洞察力。
The fungal allergen, Alternaria, is specifically associated with severe asthma, including life-threatening exacerbations. To better understand the acute innate airway response to Alternaria, naïve WT mice were challenged once intranasally with Alternaria. Naïve WT mice developed significant BAL eosinophila following Alternaria challenge when analyzed 24 hours later. In contrast to Alternaria, neither Aspergillus nor Candida induced BAL eosinophilia. Gene microarray analysis of airway epithelial cell brushings demonstrated that Alternaria-challenged naïve WT mice had an over 20 fold increase level of expression of “Found in Inflammatory Zone 1” (FIZZ1/Retnla), a resistin-like molecule. Lung immunostaining confirmed strong airway epithelial FIZZ1 expression present as early as 3 hours after a single Alternaria challenge that persisted for at least 5 days and was significantly reduced in STAT6-deficient, but not PAR-2-deficient mice. Bone marrow chimera studies revealed that STAT6 expressed in lung cells was required for epithelial FIZZ1 expression, while in contrast, STAT6 present in bone marrow derived cells contributed to airway eosinophilia. Studies investigating which cells in the non-challenged lung bind FIZZ1 demonstrated that CD45+CD11c+ (macrophages and dendritic cells) as well as collagen-1 producing CD45 negative cells (fibroblasts) can bind to FIZZ1. Importantly, direct administration of recombinant FIZZ1 to naïve WT mice led to airway eosinophilia, peribronchial fibrosis, and increased thickness of the airway epithelium. Thus, Alternaria induces STAT-6 dependent acute airway eosinophila and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness. This may provide some insight into the uniquely pathogenic aspects of Alternaria-associated asthma.
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影响因子：
14.2
作者：
Kiss, Attila;Montes, Martin;Corry, David B.
通讯作者：
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DOI：
10.4049/jimmunol.1003020
发表时间：
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期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
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