Matsuda A, Orihara K, Fukuda S, Fujinaga H, Matsumoto K, Saito H
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Allergy. 2008 Dec;63(12):1610-6. doi: 10.1111/j.1398-9995.2008.01775.x.
Some severe asthma patients are characterized by elevated levels of tumor necrosis factor alpha (TNF-alpha) and neutrophilic inflammation in the airways. Although such phenotypic changes in asthma might contribute to corticosteroid refractoriness, the role of TNF-alpha in the process remains unclear. TNF-alpha exerts its biological effects mainly by acting on the vascular endothelium, and thereby upregulates leukocyte recruitment into inflamed tissues. The aim of this study was to investigate the effects of dexamethasone (DEX) on the TNF-alpha-mediated responses of human microvascular endothelial cells from lung blood vessels (HMVEC-LBl) in vitro.
HMVEC-LBl were cultured with TNF-alpha in the presence and absence of DEX. The effects of DEX on various TNF-alpha-mediated responses, such as the expressions of chemokines and cellular adhesion molecules, leukocyte adhesion were determined.
TNF-alpha significantly induced growth-related oncogene alpha (GRO-alpha), interleukin 8 (IL-8), regulated on activation, normal T-cell expressed and secreted (RANTES) and interferon-inducible protein 10 (IP-10) productions and cell surface expressions of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on HMVEC-LBl. TNF-alpha-induced GRO-alpha and IL-8 were slightly attenuated by DEX treatment (reaches to 89% and 79%, respectively), whereas expressions of IP-10, ICAM-1 and VCAM-1 were significantly enhanced by the same treatment (up to 172%, 152% and 139%, respectively). Correspondingly, in vitro adhesion of eosinophils and neutrophils to TNF-alpha-treated HMVEC-LBl were significantly enhanced by DEX.
Some proinflammatory effects of DEX, a corticosteroid, were found in TNF-alpha-mediated in vitro reactions of pulmonary microvascular endothelial cells, i.e. chemokine productions and leukocyte adhesion. These in vitro results may explain, at least in part, the corticosteroid refractoriness accompanied by a marked increase in TNF-alpha production that is seen in severe asthmatic patients.
一些重度哮喘患者的特征是气道中肿瘤坏死因子α（TNF-α）水平升高和嗜中性粒细胞炎症。尽管哮喘中的这种表型变化可能导致皮质类固醇难治性，但TNF-α在该过程中的作用仍不清楚。TNF-α主要通过作用于血管内皮发挥其生物学效应，从而上调白细胞向炎症组织的募集。本研究的目的是在体外研究地塞米松（DEX）对来自肺血管的人微血管内皮细胞（HMVEC-LBl）的TNF-α介导反应的影响。
在有和没有DEX的情况下，将HMVEC-LBl与TNF-α一起培养。测定DEX对各种TNF-α介导反应的影响，如趋化因子和细胞粘附分子的表达、白细胞粘附。
TNF-α显著诱导HMVEC-LBl上生长相关癌基因α（GRO-α）、白细胞介素8（IL-8）、活化调节正常T细胞表达和分泌因子（RANTES）以及干扰素诱导蛋白10（IP-10）的产生和细胞表面细胞间粘附分子1（ICAM-1）和血管细胞粘附分子1（VCAM-1）的表达。DEX处理使TNF-α诱导的GRO-α和IL-8略有减弱（分别达到89%和79%），而相同处理使IP-10、ICAM-1和VCAM-1的表达显著增强（分别高达172%、152%和139%）。相应地，DEX显著增强了嗜酸性粒细胞和中性粒细胞对TNF-α处理的HMVEC-LBl的体外粘附。
在TNF-α介导的肺微血管内皮细胞体外反应中发现了皮质类固醇地塞米松的一些促炎作用，即趋化因子产生和白细胞粘附。这些体外结果可能至少部分解释了重度哮喘患者中伴随TNF-α产生显著增加的皮质类固醇难治性。
