Matsumoto K
Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki, Japan.
Verh K Acad Geneeskd Belg. 1995;57(2):109-22.
Since 1973, the occurrence of respiratory tract infections due to P. aeruginosa has increased associated with the development of broad-spectrum penicillins. A clinical entity, diffuse panbronchiolitis (DPB) is a representative disease of chronic P. aeruginosa infections in Japan. In this paper, recent advances of research on pathogenesis and treatments of chronic P. aeruginosa lower respiratory tract infections in our department are reported. We examined sputum from patients with chronic P. aeruginosa infections under the electron microscope. Mucoid type of microcolonies were observed with fibrous matrix of exopolysaccharide. Neutrophils were found to be partially surrounding the microcolony in an attempt to defense. Debris was formed mainly by the destruction of the neutrophils. Most neutrophils were found full of phagocytized debris. These data support that instead of phagocytizing bacteria, neutrophils phagocytized debris and bacteria were not completely eradicated. This might be a factor in the pathogenesis of persistent colonization of P. aeruginosa. In the airways of patients with chronic airway diseases (CAD), neutrophils enhance the recruitment of more neutrophils through the production of neutrophil chemotactic factors such as interleukin-8 (IL-8) and LTB4, perpetuating a cycle of inflammation in the lung. We demonstrated increased levels of IL-8, a chemotactic cytokine, in bronchoalveolar lavage (BAL) fluid from patients with CAD associated with P. aeruginosa infections. We also documented a significant correlation between neutrophil numbers and IL-8 levels or IL-1 beta levels or neutrophil elastase levels in BAL fluids from patients with CAD. By immunohistochemical studies and in vitro data, three major sources of IL-8 in the airways of CAD patients were found to be alveolar macrophages, bronchial epithelial cells, and migrated neutrophils. In Japan, the clinical effectiveness of oral erythromycin (EM) for CAD, including DPB seems to be established, but its pharmacological mechanism remains unclear. In addition, we found a marked decrease of IL-8 levels in BAL fluid from two patients with CAD after treatment with EM. Therefore, we postulated that EM inhibited IL-8 production by stimulated respiratory cells. EM and Roxythromycin, suppressed IL-8 production in Pseudomonas-stimulated neutrophils in a dose-dependent manner. 1 alpha, 25-dihydroxy vitamin D3 also inhibited neutrophil-derived IL-8. Our data encourage the development of new anti-IL-8 agents against persistent P. aeruginosa lower respiratory tract infections.
自1973年以来，随着广谱青霉素的发展，铜绿假单胞菌引起的呼吸道感染发生率有所增加。弥漫性泛细支气管炎（DPB）这一临床实体是日本慢性铜绿假单胞菌感染的代表性疾病。本文报道了我们科室对慢性铜绿假单胞菌下呼吸道感染的发病机制和治疗研究的最新进展。我们在电子显微镜下检查了慢性铜绿假单胞菌感染患者的痰液。观察到黏液型微菌落伴有胞外多糖的纤维基质。发现中性粒细胞部分围绕微菌落以进行防御。碎片主要由中性粒细胞的破坏形成。大多数中性粒细胞充满吞噬的碎片。这些数据支持中性粒细胞吞噬的是碎片而非细菌，且细菌未被完全根除。这可能是铜绿假单胞菌持续定植发病机制中的一个因素。在慢性气道疾病（CAD）患者的气道中，中性粒细胞通过产生中性粒细胞趋化因子如白细胞介素-8（IL-8）和白三烯B4（LTB4）增强更多中性粒细胞的募集，使肺部炎症循环持续。我们证明了在与铜绿假单胞菌感染相关的CAD患者的支气管肺泡灌洗（BAL）液中，趋化细胞因子IL-8水平升高。我们还记录了CAD患者BAL液中中性粒细胞数量与IL-8水平、IL-1β水平或中性粒细胞弹性蛋白酶水平之间存在显著相关性。通过免疫组织化学研究和体外数据，发现CAD患者气道中IL-8的三个主要来源是肺泡巨噬细胞、支气管上皮细胞和迁移的中性粒细胞。在日本，口服红霉素（EM）对包括DPB在内的CAD的临床疗效似乎已得到证实，但其药理机制仍不清楚。此外，我们发现两名CAD患者在接受EM治疗后，BAL液中IL-8水平显著下降。因此，我们推测EM通过刺激呼吸道细胞抑制IL-8的产生。EM和罗红霉素以剂量依赖的方式抑制铜绿假单胞菌刺激的中性粒细胞中IL-8的产生。1α，25-二羟基维生素D3也抑制中性粒细胞衍生的IL-8。我们的数据鼓励开发针对持续性铜绿假单胞菌下呼吸道感染的新型抗IL-8药物。
