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Lipopolysaccharide (LPS), LPS-immune complexes and cytokines as inducers of pulmonary inflammation in patients with cystic fibrosis and chronic Pseudomonas aeruginosa lung infection.

The aim of the present thesis was to summarize some important immunological mechanisms in the pathogenesis of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis (CF). The continuous presence of bacteria in the lungs induce a strong immunological response in the patients both locally in the lungs and systemically with high amounts of circulating specific anti-P. aeruginosa antibodies. Our work has been concentrating on anti-lipopolysaccharide (LPS) antibodies. We have shown an increasing antibody response in CF patients, to all three parts of the LPS molecule; lipid A, core, and O-sugars, during the course of chronic P. aeruginosa infection. The antibodies belonged to both IgA, IgM, and all four subclasses of IgG, and were detected in serum and sputum. We detected immune complexes (IC)s in sputum from chronically infected CF patients. The ICs were composed of P. aeruginosa LPS and immunoglobulins of both IgG1-4, IgA and IgM. The concentration of circulating ICs were significantly higher in chronically infected patients compared to non-infected CF patients. The presence of ICs containing LPS in sputum were positively correlated to the amount of tumor necrosis factor alpha (TNF alpha) in the same sputum sample. TNF alpha is a very potent inflammatory mediator, stimulating cells for release of several cytokines attracting polymorphonuclear neutrophil granulocytes (PMNs), which release proteolytic enzymes and toxic oxygen radicals. We detected high concentrations of both TNF alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-6, and the IL-1 receptor antagonist (IRAP) in sputum from chronically infected CF patients. The corresponding concentrations of the cytokines in serum were low or undetectable. Relatively high concentrations of serum-IRAP before the diagnosis of chronic P. aeruginosa infection were correlated to development of poor pulmonary function. We made ICs in vitro of purified P. aeruginosa LPS and hyperimmune serum from chronically infected CF patients. The biological activity of these ICs was investigated in two different assays. LPS by itself induced TNF alpha liberation in vitro, but the ICs made in vitro were also able to stimulate TNF alpha release from mononuclear cells, and they were a more potent stimuli compared to the corresponding amount of LPS alone. The IC preparation did also induce an oxidative burst response in PMNs. We conclude P. aeruginosa LPS is biological active and formation of ICs involving P. aeruginosa LPS and anti-LPS antibodies takes place in the lungs of chronically infected CF patients.(ABSTRACT TRUNCATED AT 400 WORDS)