Abstract：
Chronic allergen exposure can significantly induce p38 mitogen-activated protein kinase (MAPK) activation in asthma. p38 MAPK is involved in steroid resistance through phosphorylation of glucocorticoid receptors (GR) at S226. This study aims to investigate whether chronic allergen exposure can induce steroid resistance and whether it is associated with p38 MAPK activation in asthma. A mouse model of asthma was prepared by sensitizing and challenging mice with chronic ovalbumin (OVA) exposure. Key features of allergic asthma, encompassing bronchial hyperresponsiveness, pathology of lung tissues, cytokine profiles of inflammation in bronchoalveolar lavage fluid (BALF), and serum immunoglobulin (Ig)E concentration were evaluated. Furthermore, suppressive effects of corticosteroid on the splenocytes under stimulation of lipopolysaccharides, glucocorticoid receptor (GR) DNA binding ability of splenocytes, expression of GRα and phosphorylation of GR s226 in splenocytes, and p38 MAPK phosphorylation in splenocytes and lung tissues were determined. Chronic OVA exposure substantially induced airway hypersensitivity, leading to increased inflammatory infiltration in lung tissues. Additionally, it resulted in elevated levels of interleukin (IL)-4, IL-5, and IL-6 in BALF, as well as heightened levels of IgE in serum. Furthermore, OVA exposure substantially enhanced p38 MAPK phosphorylation in lung tissues. It also weakened the suppressive impacts of corticosteroids on splenocytes, impaired the GR DNA binding ability, and led to an enhanced phosphorylated state of GR S226 and p38 MAPK in splenocytes. Taken together, chronic allergen exposure contributes to steroid resistance in asthma, which is linked to an increased phosphorylated state of GR S226 and p38 MAPK.
摘要：
慢性变应原暴露可显著诱导哮喘患者p38丝裂原活化蛋白激酶(MAPK)活化。p38MAPK在S226通过糖皮质激素受体(GR)的磷酸化参与类固醇抗性。本研究旨在探讨慢性过敏原暴露是否可以诱导哮喘患者的激素抵抗以及是否与p38MAPK激活相关。通过用慢性卵清蛋白(OVA)暴露致敏和攻击小鼠制备哮喘小鼠模型。过敏性哮喘的主要特征，包括支气管高反应性，肺组织病理学，支气管肺泡灌洗液（BALF）中炎症的细胞因子谱，评价血清免疫球蛋白(Ig)E浓度。此外，在脂多糖刺激下，皮质类固醇对脾细胞的抑制作用，糖皮质激素受体（GR）脾细胞的DNA结合能力，脾细胞中GRα的表达和GRs226的磷酸化，并测定脾细胞和肺组织中p38MAPK的磷酸化。慢性OVA暴露显著诱导气道超敏反应，导致肺组织炎症浸润增加。此外,它导致BALF中白细胞介素（IL）-4，IL-5和IL-6的水平升高，以及血清中IgE水平升高。此外，OVA暴露显著增强了肺组织中的p38MAPK磷酸化。它还削弱了皮质类固醇对脾细胞的抑制作用，GRDNA结合能力受损，并导致脾细胞中GRS226和p38MAPK的磷酸化状态增强。一起来看,慢性过敏原暴露有助于哮喘的类固醇抵抗，与GRS226和p38MAPK的磷酸化状态增加有关。
