Role of cytokine-induced neutrophil chemoattractant-2 (cinc-2) alpha in a rat model of chronic bronchopulmonary infections with Pseudomonas aeruginosa

In order to investigate the role of the cytokine-induced neutrophil chemoat tractant (CINC) in chronic bronchopulmonary infection, we developed a rat m odel 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 bronchoalv eolar lavage (BAL) fluids in this model. The bacterial number in the lung r apidly increased from days 1 to 4, and declined 14 days after challenge. Ne utrophil number in BAL fluid increased up to one day after challenge, and t hen slowly decreased during 14 days post-challenge, Among the CINCs, the lo cal production of CINC3 alpha 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 beta nor CINC-3 were dete cted during the entire course of the infection. Increased CINC-2 mRNA expre ssion in the lung tissue after challenge was associated with CLNC-2 alpha p roduction in BAL fluid, Moreover, an immunohistochemical study demonstrated the localization of CINC-1 and CINC-2 alpha primarily in alveolar macropha ges and, to a much lesser extent, in bronchial epithelium of infected lung tissues, whereas CINC-2 beta and CINC-3 were not detected. When anti-CINC-1 or anti-CINC-2 alpha polyclonal antibodies were used for neutralizing neut rophil chemotactic activities in BAL fluids, the anti-CINC-2 alpha 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 antibo dy. These data indicate that CINC-2 alpha, which is produced by alveolar ma crophages and bronchial epithelial cells, plays a pivotal role in neutrophi l accumulation in the airway of a rat model of chronic bronchopulmonary inf ection with P. aeruginosa. (C) 2000 Academic Press.