Potential of preventing Pseudomonas aeruginosa lung infections in cystic fibrosis patients: Experimental studies in animals

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Abstract
In patients with cystic fibrosis (CF), respiratory tract infections caused by Staphylococcus aureus and Haemophilus influenzae are followed by Pseudomonas aeruginosa with increasing age. Chronic endobronchial lung infection with P. aeruginosa is the leading cause of morbidity and mortality. In Danish CF patients we noted that both onset of initial colonization and chronic lung infection with P. aeruginosa peaked during the winter months which is the season for respiratory virus infections. Virus may therefore pave the way for P. aeruginosa. We established a chronic P. aeruginosa lung infection in rats by embedding mucoid bacteria in seaweed alginate and installing the beads intratracheally into the lower part of the left lung. Although the rats did not suffer from CF, the antibody responses and the pathologic changes of the lungs mimicked the findings in CF patients. By using this model in normal and athymic rats we showed that the T-cell response during the "natural" course of the infection played no major role. In a model of acute P. aeruginosa pneumonia we found that the macroscopic inflammatory response of the lungs was immense and that the natural capacity to clear P. aeruginosa was very efficient and could not be improved by immunization, although high serum levels of IgM, IgG and IgA antibodies to P. aeruginosa alginate, LPS, exotoxin A and sonicate were induced. We developed a method for collecting and measuring IgA in saliva and noted that mucosal IgA antibodies were induced by vaccination; they did not significantly prevent inflammation, however. In the chronic rat model we succeeded to improve the survival significantly and to change the inflammatory response subsequent to vaccination from an acute type inflammation dominated by polymorphonuclear leukocytes (PMNs) as in CF patients to a chronic type inflammation dominated by mononuclear leukocytes. Furthermore, we found that rats immunized with an alginate containing vaccine had a significantly earlier cellular shift to a chronic type inflammation as well as a significant reduction in the severity of the macroscopic inflammation compared to two other vaccine groups and to nonimmunized controls. Similar results were obtained in rats treated with the TH1 cytokine, interferon-gamma (IFN-gamma). Several authors have shown that the lung tissue damage during chronic infection in CF patients is caused by a type III hypersensitivity reaction leading to release of elastase by PMNs surrounding the bacterial microcolonies. The cellular shift we have induced by vaccination and by IFN-gamma treatment therefore offers a possible new strategy for improving the clinical course in chronically infected CF patients.