Wagner Christopher, Goldmann Torsten, Rohmann Kristina, Rupp Jan, Marwitz Sebastian, Rotta Detto Loria Johannes, Limmer Stefan, Zabel Peter, Dalhoff Klaus, Drömann Daniel
Medical Clinic III, University of Schleswig-Holstein, Lx00FC;beck, Germany.
Respiration. 2015;90(5):416-25. doi: 10.1159/000439226. Epub 2015 Oct 10.
Inhaled corticosteroids (ICS) are widely used in the treatment of obstructive lung diseases. Recent data suggest a higher pneumonia risk in chronic obstructive pulmonary disease (COPD) patients treated with ICS.
Since non-typeable Haemophilus influenzae (NTHi) is the most common pathogen associated with acute exacerbations of COPD, we investigated the effects of budesonide (BUD) on NTHi-induced inflammation and invasive infection.
The alveolar epithelial cell line A549 and specimens of human lung tissue (HLT) were used in our experiments. Intracellular infection was determined by a lysis/culture assay of infected cells. Activated p38 mitogen-associated protein kinase (MAPK) was assessed using Western blotting and immunohistochemistry, expression of toll-like receptor 2 (TLR2) was determined by PCR, and CXCL-8 levels were measured using ELISA. Immunohistochemistry was used for detection of CXCL-8, platelet-activating factor receptor (PAF-R) and NTHi.
BUD significantly reduced CXCL-8 secretion in A549 cells and lung tissue infected with NTHi. Furthermore, BUD decreased the expression of PAF-R in HLT and A549 cells. In A549 cells and HLT, BUD inhibited intracellular infection and - synergistically with NTHi - increased the expression of TLR2 (in A549 cells). TLR2 stimulation did not influence the intracellular infection of A549 cells, but p38 MAPK inhibition resulted in a significant reduction of infection.
The present study adds new insights into the effects of glucocorticoids on pulmonary host defence after NTHi infection. Although the inflammatory response to infection is suppressed by BUD, interestingly, the intracellular infection is also inhibited. This effect seems to depend on the inhibition of p38 MAPK - a key enzyme in many pro-inflammatory pathways - as well as of PAF-R expression.
吸入性糖皮质激素（ICS）广泛用于阻塞性肺疾病的治疗。近期数据表明，接受ICS治疗的慢性阻塞性肺疾病（COPD）患者发生肺炎的风险更高。
鉴于不可分型流感嗜血杆菌（NTHi）是与COPD急性加重相关的最常见病原体，我们研究了布地奈德（BUD）对NTHi诱导的炎症和侵袭性感染的影响。
我们的实验使用了肺泡上皮细胞系A549和人肺组织（HLT）标本。通过对感染细胞进行裂解/培养测定来确定细胞内感染。使用蛋白质印迹法和免疫组织化学评估活化的p38丝裂原活化蛋白激酶（MAPK），通过PCR测定Toll样受体2（TLR2）的表达，并使用酶联免疫吸附测定法测量CXCL-8水平。免疫组织化学用于检测CXCL-8、血小板活化因子受体（PAF-R）和NTHi。
BUD显著降低了感染NTHi的A549细胞和肺组织中CXCL-8的分泌。此外，BUD降低了HLT和A549细胞中PAF-R的表达。在A549细胞和HLT中，BUD抑制细胞内感染，并与NTHi协同增加（A549细胞中）TLR2的表达。TLR2刺激不影响A549细胞的细胞内感染，但抑制p38 MAPK可导致感染显著减少。
本研究为糖皮质激素对NTHi感染后肺部宿主防御的影响提供了新的见解。虽然BUD抑制了对感染的炎症反应，但有趣的是，细胞内感染也受到抑制。这种作用似乎取决于对p38 MAPK（许多促炎途径中的关键酶）以及PAF-R表达的抑制。
