Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Inflammation. 2013 Aug;36(4):845-54. doi: 10.1007/s10753-013-9611-5.
Neutrophilic airway inflammation associated with multiple allergens has been related to steroid-resistant asthma. However, most animal models use only one allergen, which cannot simulate asthma closely as seen in patients. To determine the mechanism of inflammatory process involved in this severe condition, BALB/c mice were repetitively challenged with the pooled extract of dust mite, ragweed, and Aspergillus species (DRA). We found that DRA increased interleukin (IL)-10 and TGF-β levels and neutrophil recruitment in bronchial alveolar lavage fluid. We also found that although dexamethasone suppressed the release of these two cytokines, mast cells recruitment, and mucus hypersecretion, it actually increased neutrophil infiltration and the level of keratinocyte-derived chemokine (mKC), a functional homolog of human IL-8. Treatment of human lung alveolar A549 cells with Der p1, an extract of house dust mite Dermatophagoides pteronyssinus, increased the expression of IL-8 and activity of NF-κB. The elevated IL-8 level was suppressed by BAY11-7082, a selective NF-κB inhibitor, but not by dexamethasone. These results suggest that increased IL-8 (mKC) levels may be involved in steroid-resistant neutrophilic airway inflammation through an NF-κB-dependent pathway.
中性粒细胞性气道炎症与多种过敏原有关，与类固醇抵抗性哮喘有关。然而，大多数动物模型仅使用一种过敏原，无法模拟患者中所见的哮喘。为了确定这种严重情况下炎症过程的机制，我们用屋尘螨、豚草和曲霉属混合提取物（DRA）重复地对 BALB/c 小鼠进行激发。我们发现 DRA 增加了支气管肺泡灌洗液中的白细胞介素（IL）-10 和转化生长因子-β（TGF-β）水平和中性粒细胞募集。我们还发现，尽管地塞米松抑制了这两种细胞因子、肥大细胞募集和黏液高分泌的释放，但实际上它增加了中性粒细胞浸润和角质细胞衍生趋化因子（mKC）的水平，mKC 是人类白细胞介素-8（IL-8）的功能同源物。用屋尘螨 Dermatophagoides pteronyssinus 的提取物 Der p1 处理人肺泡 A549 细胞，增加了 IL-8 的表达和 NF-κB 的活性。选择性 NF-κB 抑制剂 BAY11-7082 抑制了升高的 IL-8 水平，但地塞米松不能抑制。这些结果表明，通过 NF-κB 依赖性途径，升高的 IL-8（mKC）水平可能与类固醇抵抗性中性粒细胞性气道炎症有关。
