Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite.
Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite.
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DOI：
10.1371/journal.pone.0051268
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Chen ZG;Zhang TT;Li HT;Chen FH;Zou XL;Ji JZ;Chen H
慢性变应性哮喘以Th 2型炎症为特征，参与气道重塑和肺功能恶化。然而，连接气道炎症和重塑的起始因素尚不清楚。胸腺基质淋巴细胞生成素（Thymic stromal lymphopoietin，TSLP）是一种上皮细胞源性细胞因子，可通过TSLP-TSLPR和OX 40 L-OX 40信号通路强烈激活肺树突状细胞（dendritic cells，DC），促进Th 2细胞分化。为了确定TSLP是否是慢性过敏原诱导的哮喘中气道重塑的潜在触发因素，我们通过鼻内给予屋尘螨（HDM）提取物连续5周诱导小鼠过敏性气道炎症。我们发现，反复呼吸道暴露于HDM可引起显著的气道嗜酸性粒细胞炎症、支气管周围胶原沉积、杯状细胞增生和对乙酰甲胆碱的气道高反应性（AHR）。这些作用伴随着显著的Th 2应答，其特征在于Th 2型细胞因子（如IL-4和IL-13）以及转录因子加塔-3的上调。气道TSLP和转化生长因子β 1（TGF-β1）水平升高。我们进一步证明，使用慢性HDM诱导的哮喘模型，通过用抗TSLP mAb中和TSLP来抑制Th 2应答逆转了气道炎症，防止了结构改变，并降低了乙酰甲胆碱和TGF-β1水平的AHR。这些结果表明，TSLP在慢性过敏性哮喘气道炎症和重塑的启动和持续中起着关键作用。
Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs) through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR) to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-β1) were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-β1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.
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DOI：
10.1084/jem.20062211
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Allakhverdi Z;Comeau MR;Jessup HK;Yoon BR;Brewer A;Chartier S;Paquette N;Ziegler SF;Sarfati M;Delespesse G
通讯作者：
Delespesse G
影响因子：
5.8
作者：
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Epstein MM
DOI：
10.1164/rccm.200308-1094oc
发表时间：
2004-02-01
影响因子：
24.7
作者：
Johnson, JR;Wiley, RE;Jordana, M
通讯作者：
Jordana, M
DOI：
10.1165/ajrcmb.17.3.2733
发表时间：
1997-09-01
影响因子：
6.4
作者：
Minshall, EM;Leung, DYM;Hamid, Q
通讯作者：
Hamid, Q
影响因子：
4.4
作者：
McMillan, SJ;Xanthou, G;Lloyd, CM
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Lloyd, CM