Corticosteroid insensitivity persists in the absence of STAT1 signaling in severe allergic airway inflammation.
Corticosteroid insensitivity persists in the absence of STAT1 signaling in severe allergic airway inflammation.
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DOI：
10.1152/ajplung.00244.2021
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Britt RD Jr
中科院分区：
文献类型：
--
作者：
Lewis BW;Jackson D;Amici SA;Walum J;Guessas M;Guessas S;Coneglio E;Boda AV;Guerau-de-Arellano M;Grayson MH;Britt RD Jr
哮喘中的皮质类固醇不敏感限制了有效治疗严重哮喘的能力，尽管进行了皮质类固醇治疗，但严重哮喘的特点仍是持续性气道炎症、气道高反应性 (AHR) 和气流阻塞。最近的报告表明，皮质类固醇不敏感与重度哮喘中干扰素-γ (IFN-γ) 水平升高和辅助性 T (Th) 1 淋巴细胞浸润有关。 IFN-γ 激活信号转导和转录激活因子 1 (STAT1) 是 Th1 炎症中的关键信号通路；然而，其在严重过敏性气道炎症和皮质类固醇敏感性中的作用仍不清楚。在这项研究中，我们用混合过敏原 (MA) 挑战野生型 (WT) 和 Stat1−/− 小鼠，并添加 c-di-GMP [双-(3'-5')-环状二聚鸟苷单磷酸]，这是一种 Th1 细胞浸润的诱导剂，嗜酸性粒细胞、中性粒细胞、Th1、Th2 和 Th17 细胞增加。与 WT 小鼠相比，Stat1−/− 的中性粒细胞、Th1 和 Th17 细胞浸润减少。为了评估皮质类固醇敏感性，用载体、1 或 3 mg/kg 丙酸氟替卡松 (FP) 治疗小鼠。皮质类固醇显着降低 c-di-GMP + MA 攻击的 WT 和 Stat1−/− 小鼠中的嗜酸性粒细胞浸润和细胞因子水平。然而，组织学和功能分析表明，皮质类固醇并不能减少 c-di-GMP + MA 攻击的 WT 或 Stat1−/− 小鼠的气道炎症、上皮粘液细胞丰度、气道平滑肌质量和 AHR。总的来说，我们的数据表明 Th1 炎症的增加与皮质类固醇敏感性的降低有关。然而，在 STAT1 缺失的情况下，气道病理学和 AHR 的持续增加表明结构性气道细胞中的皮质类固醇不敏感是一个独立于 STAT1 的过程。
Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-γ (IFN-γ) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal transducer and activator of transcription 1 (STAT1) activation by IFN-γ is a key signaling pathway in Th1 inflammation; however, its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear. In this study, we challenged wild-type (WT) and Stat1−/− mice with mixed allergens (MA) augmented with c-di-GMP [bis-(3′-5′)-cyclic dimeric guanosine monophosphate], an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared with WT mice, Stat1−/− had reduced neutrophils, Th1, and Th17 cell infiltration. To evaluate corticosteroid sensitivity, mice were treated with either vehicle, 1 or 3 mg/kg fluticasone propionate (FP). Corticosteroids significantly reduced eosinophil infiltration and cytokine levels in both c-di-GMP + MA-challenged WT and Stat1−/− mice. However, histological and functional analyses show that corticosteroids did not reduce airway inflammation, epithelial mucous cell abundance, airway smooth muscle mass, and AHR in c-di-GMP + MA-challenged WT or Stat1−/− mice. Collectively, our data suggest that increased Th1 inflammation is associated with a decrease in corticosteroid sensitivity. However, increased airway pathology and AHR persist in the absence of STAT1 indicate corticosteroid insensitivity in structural airway cells is a STAT1 independent process.
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影响因子：
24.3
作者：
Bossley, C. J.;Saglani, S.;Bush, A.
通讯作者：
Bush, A.
影响因子：
14.2
作者：
Cui, JQ;Pazdziorko, S;Marusic, S
通讯作者：
Marusic, S
DOI：
10.1038/labinvest.2015.72
发表时间：
2015-08
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
Guest IC;Sell S
通讯作者：
Sell S
影响因子：
56.9
作者：
Finotto, S;Neurath, MF;Glimcher, LH
通讯作者：
Glimcher, LH
影响因子：
10
作者：
Berry, Mike;Morgan, Angela;Pavord, Ian D.
通讯作者：
Pavord, Ian D.