Oishi K, Sonoda F, Kobayashi S, Iwagaki A, Nagatake T, Matsushima K, Matsumoto K
Department of Internal Medicine, Nagasaki University, Japan.
Infect Immun. 1994 Oct;62(10):4145-52. doi: 10.1128/iai.62.10.4145-4152.1994.
To evaluate of the role of interleukin-8 (IL-8), a chemotactic cytokine, in the continuous neutrophil accumulation in the airways of patients with chronic airway disease (CAD) and persistent Pseudomonas aeruginosa infection, we investigated the cell population, IL-8 levels, IL-1 beta levels, tumor necrosis factor (TNF) activities, and neutrophil elastase (NE) activities of bronchoalveolar lavage (BAL) fluids in 17 CAD patients (with P. aeruginosa infections [CAD+PA], n = 9; without any bacterial infections [CAD-PA], n = 8) and 8 normal volunteers. We found significant elevations of neutrophil numbers, IL-8/albumin ratios, and NE/albumin ratios in BAL fluids from CAD patients, in the following rank order: CAD+PA > CAD-PA > normal volunteers. IL-1 beta/albumin ratios were elevated only in CAD+PA, while no TNF bioactivity was detected in BAL fluids. The neutrophil numbers correlated significantly with the IL-8/albumin ratios and NE/albumin ratios in the BAL fluids of CAD patients. When anti-human IL-8 immunoglobulin G was used for neutralizing neutrophil chemotactic factor (NCF) activities in BAL fluids, the mean reduction rate of NCF activities in CAD+PA patients was significantly higher than that in CAD-PA patients. We also evaluated the effects of low-dose, long-term erythromycin therapy in BAL fluids from three CAD+PA and two CAD-PA patients. Treatment with erythromycin caused significant reductions of neutrophil numbers, IL-8/albumin ratios, and NE/albumin ratios in BAL fluids from these patients. To elucidate the mechanism of erythromycin therapy, we also examined whether erythromycin suppressed IL-8 production by human alveolar macrophages and neutrophils in vitro. We demonstrated a moderate inhibitory effect of erythromycin on IL-8 production in Pseudomonas-stimulated neutrophils but not in alveolar macrophages. Our data support the view that persistent P. aeruginosa infection enhances IL-8 production and IL-8-derived NCF activity, causing neutrophil accumulation in the airways and the progressive lung injuries observed in patients with CAD. The clinical efficacy of erythromycin therapy for CAD patients might be partly mediated through a reduced IL-8 production, diminishing neutrophil accumulation and NE release in the airways.
为评估趋化细胞因子白细胞介素-8（IL-8）在慢性气道疾病（CAD）合并持续性铜绿假单胞菌感染患者气道中中性粒细胞持续积聚中的作用，我们调查了17例CAD患者（合并铜绿假单胞菌感染[CAD+PA]，n = 9；无任何细菌感染[CAD-PA]，n = 8）和8名正常志愿者支气管肺泡灌洗（BAL）液中的细胞群体、IL-8水平、IL-1β水平、肿瘤坏死因子（TNF）活性和中性粒细胞弹性蛋白酶（NE）活性。我们发现CAD患者BAL液中中性粒细胞数量、IL-8/白蛋白比值和NE/白蛋白比值显著升高，顺序如下：CAD+PA＞CAD-PA＞正常志愿者。IL-1β/白蛋白比值仅在CAD+PA中升高，而在BAL液中未检测到TNF生物活性。CAD患者BAL液中的中性粒细胞数量与IL-8/白蛋白比值和NE/白蛋白比值显著相关。当使用抗人IL-8免疫球蛋白G中和BAL液中的中性粒细胞趋化因子（NCF）活性时，CAD+PA患者中NCF活性的平均降低率显著高于CAD-PA患者。我们还评估了低剂量、长期红霉素治疗对3例CAD+PA和2例CAD-PA患者BAL液的影响。红霉素治疗导致这些患者BAL液中的中性粒细胞数量、IL-8/白蛋白比值和NE/白蛋白比值显著降低。为阐明红霉素治疗的机制，我们还检测了红霉素在体外是否抑制人肺泡巨噬细胞和中性粒细胞产生IL-8。我们证明红霉素对铜绿假单胞菌刺激的中性粒细胞产生IL-8有中度抑制作用，但对肺泡巨噬细胞无此作用。我们的数据支持以下观点：持续性铜绿假单胞菌感染增强IL-8产生和IL-8衍生的NCF活性，导致CAD患者气道中的中性粒细胞积聚和进行性肺损伤。红霉素治疗CAD患者的临床疗效可能部分是通过减少IL-8产生、减少气道中的中性粒细胞积聚和NE释放来介导的。
