Lee E, Lindo T, Jackson N, Meng-Choong L, Reynolds P, Hill A, Haswell M, Jackson S, Kilfeather S
Institute of Cardiovascular and Respiratory Pharmaceutical Development, School of Sciences, University of Sunderland, Sunderland, UK.
Am J Respir Crit Care Med. 1999 Dec;160(6):2079-85. doi: 10.1164/ajrccm.160.6.9903136.
Persistent neutrophilia is a feature of chronic obstructive pulmonary disease (COPD). Leukotriene synthesis inhibitors and cysteinyl leukotriene receptor antagonists have shown efficacy in the treatment of asthma. Antagonism of leukotriene (LT)B(4) receptors is being considered as a mode of treating COPD. We examined the capacity for inhibition of leukotriene synthesis and LTB(4) receptor antagonism to reduce survival of neutrophils from patients with COPD and those from normal subjects. The basal apoptosis level of these cells was 55.4 +/- 2.4% (mean +/- SEM) of total cells. Separate exposure to lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), dexamethasone (DEX), and LTB(4) increased neutrophil survival (p < 0. 001). The LTB(4) receptor antagonist SB201146 abolished LPS-induced survival in a concentration-dependent manner (10 pmol to 0.1 microM), with an IC(50) of 1.9 nM. Combined exposure to SB201146 and to the cysteinyl leukotriene antagonist SKF104353 did not have a greater effect on survival than did exposure to SB201146 alone. Inhibition of 5-lipoxygenase (5-LO) with BWA4C and of 5-LO-activating protein (FLAP) with MK886 abolished GM-CSF- and DEX-induced neutrophil survival. BWA4C and MK886 abolished GM-CSF- induced neotrophil survival in a concentration-dependent manner (1 nM to 10 microM), with IC(50) values of 182.0 nM and 63.1 nM, respectively. These findings demonstrate reversal of LPS-, GM-CSF-, and DEX-induced neutrophil survival by LTB(4) receptor antagonism and inhibitors of 5-LO and FLAP. They also suggest a potential additional antiinflammatory mode of action of these compounds through reduction of cell survival.
持续性中性粒细胞增多是慢性阻塞性肺疾病（COPD）的一个特征。白三烯合成抑制剂和半胱氨酰白三烯受体拮抗剂已显示出对哮喘治疗有效。白三烯（LT）B4受体拮抗作用正被视为治疗COPD的一种方式。我们研究了抑制白三烯合成和LTB4受体拮抗作用降低COPD患者及正常受试者中性粒细胞存活率的能力。这些细胞的基础凋亡水平为总细胞数的55.4±2.4%（平均值±标准误）。单独暴露于脂多糖（LPS）、粒细胞巨噬细胞集落刺激因子（GM-CSF）、地塞米松（DEX）和LTB4可提高中性粒细胞存活率（p<0.001）。LTB4受体拮抗剂SB201146以浓度依赖性方式（10 pmol至0.1 μM）消除LPS诱导的存活率，半数抑制浓度（IC50）为1.9 nM。联合暴露于SB201146和半胱氨酰白三烯拮抗剂SKF104353对存活率的影响并不比单独暴露于SB201146时更大。用BWA4C抑制5-脂氧合酶（5-LO）以及用MK886抑制5-LO激活蛋白（FLAP）可消除GM-CSF和DEX诱导的中性粒细胞存活率。BWA4C和MK886以浓度依赖性方式（1 nM至10 μM）消除GM-CSF诱导的中性粒细胞存活率，IC50值分别为182.0 nM和63.1 nM。这些发现表明，通过LTB4受体拮抗作用以及5-LO和FLAP抑制剂可逆转LPS、GM-CSF和DEX诱导的中性粒细胞存活率。它们还提示这些化合物可能通过降低细胞存活率而具有额外的抗炎作用方式。
