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New approaches to Pseudomonas aeruginosa lower respiratory tract infections
1Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki, Japan.
Abstract:
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.
Insights
Chronic Pseudomonas aeruginosa infections, common in diffuse panbronchiolitis (DPB), involve neutrophils phagocytizing debris instead of bacteria. This study explores new treatments targeting interleukin-8 (IL-8) to combat persistent lung infections.
Area of Science:
- Pulmonology and Infectious Diseases
- Microbiology and Immunology
Background:
- Increasing respiratory tract infections caused by Pseudomonas aeruginosa (P. aeruginosa) since the advent of broad-spectrum penicillins.
- Diffuse panbronchiolitis (DPB), a chronic P. aeruginosa infection prevalent in Japan, serves as a key clinical model.
- Understanding the pathogenesis of chronic P. aeruginosa lower respiratory tract infections is crucial for effective treatment.
Purpose of the Study:
- To investigate the pathogenesis of chronic P. aeruginosa lower respiratory tract infections.
- To identify the role of neutrophils and inflammatory mediators like interleukin-8 (IL-8) in persistent infections.
- To explore potential therapeutic strategies, including the mechanism of erythromycin (EM) and other agents.
Main Methods:
- Electron microscopy of sputum from patients with chronic P. aeruginosa infections.
- Measurement of inflammatory cytokines (IL-8, IL-1 beta) and neutrophil elastase in bronchoalveolar lavage (BAL) fluid.
- Immunohistochemical studies and in vitro experiments on IL-8 production by respiratory cells and neutrophils.
- Assessment of the effect of erythromycin (EM), roxythromycin, and vitamin D3 on IL-8 production.
Main Results:
- Neutrophils in infected airways were observed to phagocytize debris rather than bacteria, contributing to persistent P. aeruginosa colonization.
- Elevated levels of IL-8, IL-1 beta, and neutrophil elastase were found in BAL fluid of patients with chronic airway diseases (CAD) and P. aeruginosa infections.
- Alveolar macrophages, bronchial epithelial cells, and neutrophils were identified as major sources of IL-8.
- Oral erythromycin (EM) treatment led to decreased IL-8 levels and suppressed IL-8 production in vitro, suggesting a novel anti-inflammatory mechanism.
Conclusions:
- Neutrophil dysfunction in phagocytizing bacteria and the resulting inflammatory cycle mediated by IL-8 are key factors in chronic P. aeruginosa lung infections.
- Erythromycin (EM) and other agents demonstrate potential therapeutic value by inhibiting IL-8 production.
- Targeting IL-8 represents a promising strategy for developing new treatments against persistent P. aeruginosa lower respiratory tract infections.