Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor γ Regulates Inflammation and Mucin Expression in Allergic Airway Disease.
Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor γ Regulates Inflammation and Mucin Expression in Allergic Airway Disease.
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DOI：
10.4049/jimmunol.1800649
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发表时间：
2018-09-15
期刊：
影响因子：
--
通讯作者：
Reddy RC
中科院分区：
文献类型：
--
作者：
Lakshmi SP;Reddy AT;Banno A;Reddy RC
呼吸道上皮细胞(AECs)对进入呼吸系统的空气中的刺激物进行炎症反应。由呼吸道上皮中的杯状细胞产生的粘液层也通过其提供的物理和化学屏障而有助于生理防御机制。这些功能的失调或损害被认为是构成哮喘主要病理特征的慢性炎症和组织重塑的原因之一。特别是，粘液高分泌导致呼吸道阻塞和肺功能受损与哮喘患者的发病率和死亡率有关。过氧化物酶体增殖物激活受体γ(PPARγ)是一种配体激活的转录因子，参与多种细胞过程。越来越多的证据表明，PPARγ激动剂可以拮抗过度的炎症反应，但PPARγ在气道重塑/粘液高分泌中的确切作用尚不清楚。在这项研究中，我们创建了AEC特异性的PPARγ缺失，以研究PPARγ的S在过敏性呼吸道疾病小鼠模型中的功能。AEC特异性PPARγ缺陷加重了气道高反应性、炎症、细胞因子表达和组织重塑。我们还发现，PPARγ直接与在MUC5AC中发现的PPAR反应元件结合并抑制基因表达。同样，PPARγ调节原代人支气管上皮细胞中的粘蛋白和炎症因子。鉴于目前标准疗法对呼吸道粘液高分泌的直接作用有限和不足，我们的研究表明，AEC-PPARγ的S作为MUC5AC的转录抑制因子，突显了该受体作为哮喘药物靶点的潜力。
Airway epithelial cells (AECs) orchestrate inflammatory responses to airborne irritants that enter the respiratory system. A viscous mucus layer produced by goblet cells in the airway epithelium also contributes to a physiological defense mechanism through the physical and chemical barriers it provides. Dysregulation or impairment in these functions has been implicated as a cause of the chronic inflammation and tissue remodeling that constitute major pathological features of asthma. In particular, mucus hypersecretion leading to airway obstruction and impaired pulmonary function is associated with morbidity and mortality in asthma patients. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor involved in a variety of cellular processes. Accumulating evidence indicates that PPARγ agonists antagonize exaggerated inflammatory responses, yet PPARγ’s precise role in airway remodeling/mucus hypersecretion has yet to be defined. In this study, we created an AEC-specific PPARγ deletion to investigate PPARγ’s functions in a murine model of allergic airway disease. AEC-specific PPARγ deficiency exaggerated airway hyperresponsiveness, inflammation, cytokine expression, and tissue remodeling. We also found that PPARγ directly bound to a PPAR response element found in MUC5AC and repressed gene expression. Likewise, PPARγ regulated mucin and inflammatory factors in primary human bronchial epithelial cells. In light of the current standard therapies’ limited and inadequate direct effect on airway mucus hypersecretion, our study showing AEC-PPARγ’s role as a transcriptional repressor of MUC5AC highlights this receptor’s potential as a pharmacological target for asthma.
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DOI：
10.1056/nejmra0910061
发表时间：
2010-12-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Fahy JV;Dickey BF
通讯作者：
Dickey BF
影响因子：
2.9
作者：
Shen Y;Chen L;Wang T;Wen F
通讯作者：
Wen F
影响因子：
1.2
作者：
Reddy, Aravind T.;Lakshmi, Sowmya P.;Reddy, Raju C.
通讯作者：
Reddy, Raju C.
影响因子：
5.8
作者：
Narala VR;Ranga R;Smith MR;Berlin AA;Standiford TJ;Lukacs NW;Reddy RC
通讯作者：
Reddy RC
影响因子：
78.5
作者：
Kufe, Donald W.
通讯作者：
Kufe, Donald W.