Meliton A Y, Muñoz N M, Lambertino A, Boetticher E, Learoyd J, Zhu X, Leff A R
Dept of Medicine, MC6076, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Eur Respir J. 2006 Nov;28(5):920-8. doi: 10.1183/09031936.06.00028406. Epub 2006 Jun 28.
Phosphodiesterase (PDE)4 inhibition attenuates neutrophilic inflammation in chronic obstructive pulmonary disease. The objective of the present study was to examine the efficacy and mechanism by which PDE4 inhibition blocks adhesion of beta(2)-integrin to an endothelial counterligand. Neutrophils (polymorphonuclear leukocytes (PMNs)) were isolated from humans receiving no medication. Adhesion was analysed by myeloperoxidase activity. The effects of cilomilast+/-salmeterol on the following were determined: 1) surface CD11b expression; 2) adhesion; 3) intracellular cyclic adenosine monophosphate (cAMP) concentration; and 4) extracellular signal-regulated kinase (ERK)-1/2-mediated group IVA-phospholipase A(2) (gIVA-PLA(2)) phosphorylation caused by leukotriene (LT)B(4) or tumour necrosis factor (TNF)-alpha activation. Either cilomilast or rolipram+/-salmeterol caused concentration-related blockade of LTB(4)-induced adhesion to counterligand, but had no effect on TNF-alpha-activated PMNs. A comparable increase in intracellular cAMP concentration for PMNs activated with LTB(4) and TNF-alpha was caused by 1 muM cilomilast and 0.1 microM salmeterol. Upregulation of surface CD11b expression and ERK-1/2 phosphorylation were blocked by cilomilast or rolipram+/-salmeterol for PMNs activated by LTB(4), but not for cells stimulated by TNF-alpha. Cilomilast+/-salmeterol also blocked gIVA-PLA(2) phosphorylation caused by LTB(4) but not TNF-alpha. In conclusion, the current study demonstrates that both leukotriene B(4) and tumour necrosis factor-alpha upregulate cyclic adenosine monophosphate. However, cyclic adenosine monophosphate does not block beta(2)-integrin adhesion caused by tumour necrosis factor-alpha. It was concluded that tumour necrosis factor-alpha prevents inhibition of extracellular signal-regulated kinase-1/2-mediated group IVA-phospholipase A(2) activation, which is essential for beta(2)-integrin adhesion in polymorphonuclear leukocytes.
磷酸二酯酶（PDE）4抑制可减轻慢性阻塞性肺疾病中的中性粒细胞炎症。本研究的目的是探讨PDE4抑制阻断β2整合素与内皮细胞配体黏附的疗效和机制。从未接受药物治疗的人类受试者中分离出中性粒细胞（多形核白细胞（PMN））。通过髓过氧化物酶活性分析黏附情况。确定了西洛司特±沙美特罗对以下各项的影响：1）表面CD11b表达；2）黏附；3）细胞内环磷酸腺苷（cAMP）浓度；4）由白三烯（LT）B4或肿瘤坏死因子（TNF）-α激活引起的细胞外信号调节激酶（ERK）-1/2介导的IVA组磷脂酶A2（gIVA-PLA2）磷酸化。西洛司特或咯利普兰±沙美特罗均可导致LTB4诱导的与配体黏附的浓度依赖性阻断，但对TNF-α激活的PMN无作用。1 μM西洛司特和0.1 μM沙美特罗可使LTB4和TNF-α激活的PMN细胞内cAMP浓度出现类似升高。西洛司特或咯利普兰±沙美特罗可阻断LTB4激活的PMN表面CD11b表达上调和ERK-1/2磷酸化，但对TNF-α刺激的细胞无此作用。西洛司特±沙美特罗还可阻断LTB4引起的gIVA-PLA2磷酸化，但不能阻断TNF-α引起的磷酸化。总之，本研究表明白三烯B4和肿瘤坏死因子-α均可上调环磷酸腺苷。然而，环磷酸腺苷不能阻断肿瘤坏死因子-α引起的β2整合素黏附。得出的结论是，肿瘤坏死因子-α可阻止细胞外信号调节激酶-1/2介导的IVA组磷脂酶A2激活的抑制，而这对于多形核白细胞中β2整合素黏附至关重要。
