ROLE OF CYTOKINE-INDUCED NEUTROPHIL CHEMOATTRACTANT-2 (CINC-2) α IN A RAT MODEL OF CHRONIC BRONCHOPULMONARY INFECTIONS WITH PSEUDOMONAS AERUGINOSA

Abstract

In order to investigate the role of the cytokine-induced neutrophil chemoattractant (CINC) in chronic bronchopulmonary infection, we developed a rat model of bronchopulmonary infection with Pseudomonas aeruginosa by using the agar bead method, and determined the kinetics of bacterial and cell number, as well as the concentrations of CINC-1, CINC-2, and CINC-3 in bronchoalveolar lavage (BAL) fluids in this model. The bacterial number in the lung rapidly increased from days 1 to 4, and declined 14 days after challenge. Neutrophil number in BAL fluid increased up to one day after challenge, and then slowly decreased during 14 days post-challenge. Among the CINCs, the local production of CINC-2 α sharply increased at day 1 and then decreased until day 4 post-challenge, while the local production of CINC-1 slightly increased at day 1 post-challenge. Neither CINC-2 β nor CINC-3 were detected during the entire course of the infection. Increased CINC-2 mRNA expression in the lung tissue after challenge was associated with CINC-2 α production in BAL fluid. Moreover, an immunohistochemical study demonstrated the localization of CINC-1 and CINC-2 α primarily in alveolar macrophages and, to a much lesser extent, in bronchial epithelium of infected lung tissues, whereas CINC-2 β and CINC-3 were not detected. When anti-CINC-1 or anti-CINC-2 α polyclonal antibodies were used for neutralizing neutrophil chemotactic activities in BAL fluids, the anti-CINC-2 α antibody inhibited 70% of the chemotactic activity in BAL fluids from infected rats at day 1 after challenge. No inhibition was observed by anti-CINC-1 antibody. These data indicate that CINC-2 α, which is produced by alveolar macrophages and bronchial epithelial cells, plays a pivotal role in neutrophil accumulation in the airway of a rat model of chronic bronchopulmonary infection with P. aeruginosa.