STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration.
STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration.
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STAT3 和 IL-6 在 OVA 和臭氧诱导的中性粒细胞浸润哮喘模型中导致皮质类固醇抵抗
DOI：
10.3389/fmolb.2021.717962
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发表时间：
2021
影响因子：
5
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Xue Y;Zhou Y;Bao W;Fu Q;Hao H;Han L;Zhang X;Tian X;Zhang M
暴露于高浓度臭氧会导致哮喘治疗中对糖皮质激素不敏感，但其潜在机制尚不清楚。我们构建了两种哮喘模型：通过卵清蛋白（OVA）致敏/激发建立 “T2高” 哮喘模型，而OVA致敏/激发联合臭氧暴露（OVA + 臭氧）用于诱导气道炎症，同时增加中性粒细胞数量以模拟 “T2低” 哮喘。通过细胞因子抗体芯片检测辅助性T（Th）1/2/17相关细胞因子的表达。进行支气管激发试验以评估小鼠的肺阻力。采用苏木精 - 伊红染色、过碘酸 - 希夫染色以及α - 平滑肌肌动蛋白的免疫组织化学（IHC）分析来观察肺部的形态学变化。通过蛋白质免疫印迹法检测糖皮质激素受体（GRs）和磷酸化GR（p - GR）的表达。通过逆转录 - 实时定量聚合酶链反应（RT - qPCR）对Nr3c1 mRNA进行定量。通过酶联免疫吸附试验（ELISAs）、蛋白质免疫印迹法或免疫组织化学分析检测促炎细胞因子、信号转导及转录激活因子3（STAT3）、细胞因子信号转导抑制因子3（SOCS3）和趋化因子CXCL1的蛋白表达。对7名哮喘患者和10名因肺结节接受开胸手术的健康对照者切除的肺组织进行免疫组织化学分析和酶联免疫吸附试验评估。在两种哮喘模型中，与对照组相比，均出现黏液高分泌以及气道炎症、高反应性和重塑，而OVA + 臭氧组显示出严重的中性粒细胞浸润。在OVA + 臭氧组中，Th17相关细胞因子（白细胞介素（IL）-6、IL - 17A、IL - 21）、GR蛋白和CXCL1的表达增加，而p - GR的表达降低。地塞米松（Dex）不能完全逆转OVA + 臭氧组中p - GR和组蛋白去乙酰化酶 - 2的表达。OVA + 臭氧组中STAT3表达增加，且不能被地塞米松完全逆转，IL - 6的表达同样如此。IL - 6或IL - 17A与STAT3呈正相关，SOCS3与STAT3呈负相关，这表明IL - 6/STAT3通路可能参与了OVA + 臭氧诱导的糖皮质激素抵抗性气道炎症。在临床样本中，肺组织中IL - 17A的表达与STAT3阳性区域百分比呈正相关，与SOCS3表达呈负相关。IL - 6/STAT3通路可能通过调节Th17细胞导致OVA + 臭氧诱导的中性粒细胞性气道炎症中糖皮质激素不敏感，这可为哮喘糖皮质激素抵抗的个体化治疗提供新靶点。
Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate “T2-low” asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone–induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone–induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma.
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臭氧反复短时间暴露对卵清蛋白诱发哮喘小鼠模型气道/肺部炎症、气道高反应性和粘液产生的影响
影响因子：
7.5
作者：
Bao, Wuping;Zhang, Yingying;Zhou, Xin
通讯作者：
Zhou, Xin
影响因子：
2.1
作者：
Last, JA;Ward, R;Kenyon, NJ
通讯作者：
Kenyon, NJ
影响因子：
5
作者：
Pinheiro, Nathalia M.;Miranda, Claudia J. C. P.;Prado, Carla M.
通讯作者：
Prado, Carla M.
DOI：
10.12659/msm.881759
发表时间：
2011-05
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Lan F;Liu K;Zhang J;Qi Y;Li K;Lin P
通讯作者：
Lin P
影响因子：
5.8
作者：
Halwani R;Sultana A;Al-Kufaidy R;Jamhawi A;Vazquez-Tello A;Al-Muhsen S
通讯作者：
Al-Muhsen S