Peptides, Pseudomonas aeruginosa, polysaccharides and lipopolysaccharides--players in the predicament of cystic fibrosis patients.

Finally, there is the issue of how relevant the changes in P. aeruginosa LPS during growth in the CF lung are to the complex pathological picture of CF. The hypothesis that defects in the activity of AMPs underlie hypersusceptibility of CF patients to P. aeruginosa infection was initiated by Welsh and colleagues18xCystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Smith, J.J et al. Cell. 1996; 85: 229–236Abstract | Full Text | Full Text PDF | PubMed | Scopus (780)See all References18, who reported that airway surface liquid (ASL) from CF patients failed to kill P. aeruginosa because the high Cl− content inactivated a putative salt-sensitive AMP. However, these workers had difficulty reproducing the measurements of the Cl− content of nasal secretions from CF patients, and others have reported no difference in salt content between normal and CF ASL (Ref. 19xIon composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects. Knowles, M.R et al. J. Clin. Invest. 1997; 100: 2588–2595Crossref | PubMedSee all ReferencesRef. 19). Follow-up work by Welsh and colleagues found lysozyme and lactoferrin to be the predominant antimicrobial factors in ASL (Ref. 20xActivity of abundant antimicrobials of the human airway. Travis, S.M et al. Am. J. Respir. Cell. Mol. Biol. 1999; 20: 872–879Crossref | PubMedSee all ReferencesRef. 20), and although there was some effect of high salt levels on the antimicrobial activity of individual factors, this effect could be compensated for by increased concentrations of these factors. Thus, no unique salt content was found to inhibit the antimicrobial activity of CF ASL. Additional papers on the potential role of AMP in hypersusceptibility of CF patients to P. aeruginosa infection have made some associations18xCystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Smith, J.J et al. Cell. 1996; 85: 229–236Abstract | Full Text | Full Text PDF | PubMed | Scopus (780)See all References, 20xActivity of abundant antimicrobials of the human airway. Travis, S.M et al. Am. J. Respir. Cell. Mol. Biol. 1999; 20: 872–879Crossref | PubMedSee all References, 21xProduction of beta-defensins by human airway epithelia. Singh, P.K et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 14 961—14 966See all References, 22xHuman β-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Goldman, M.J et al. Cell. 1997; 88: 553–560Abstract | Full Text | Full Text PDF | PubMed | Scopus (776)See all References, but no definitive study of these factors in relation to CF airway disease has been reported. A major problem with the hypothesis is it fails to account for the overwhelming role of P. aeruginosa in CF airway disease–by young adulthood, >80% of CF patients are chronically infected with mucoid P. aeruginosa23xSee all References23. One would anticipate a defect in an innate defence mechanism, such as AMPs, to increase susceptibility to a multitude of pathogens, but it is clearly P. aeruginosa, and specifically mucoid P. aeruginosa, which gives rise to severe pulmonary decline in CF (Ref. 24xGender differences in cystic fibrosis: Pseudomonas aeruginosa infection. Demko, C.A et al. J. Clin. Epidemiol. 1995; 48: 1041–1049Abstract | Full Text PDF | PubMed | Scopus (179)See all ReferencesRef. 24).Staphylococcus aureus, the other common CF pathogen, has never been shown to affect pulmonary decline in CF significantly25xSystematic review of anti-staphylococcal antibiotic therapy in cystic fibrosis. McCaffery, K et al. Thorax. 1999; 54: 380–383Crossref | PubMedSee all References25 and, although a small number of CF patients occasionally contract significant S. aureus lung infections such as empyema and pneumonia, the chronic carriage of S. aureus by some CF patients, as detected by throat culture, has not been shown to affect pulmonary function. Indeed, in an unpublished study of daily anti-staphylococcal prophylaxis in CF patients, no clinical benefit was found, in spite of the dramatic suppression of recovery of S. aureus from CF throat cultures (H. Stutman, unpublished). Thus, the biological implications for increased resistance of CF isolates to AMP are unclear. As for the increased induction of IL-8 by LPS from P. aeruginosa CF isolates, two factors not evaluated by Ernst et al. were the effects of loss of O side chain production by CF isolates6xPseudomonas aeruginosa isolates from patients with cystic fibrosis: a class of serum-sensitive, non-typable strains deficient in lipopolysaccharide O side chains. Hancock, R.E.W et al. Infect. Immun. 1983; 42: 170–177PubMedSee all References6 and the role of antibodies to P. aeruginosa LPS. CF patients have very high titers of antibody to this structure in both serum and sputum1xMicrobial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia. Govan, J.R and Deretic, V. Microbiol. Rev. 1996; 60: 539–574PubMedSee all References, 26xCirculating immune complexes, antibodies to Pseudomonas aeruginosa and pulmonary status in cystic fibrosis. Lagace, J et al. J. Clin. Lab. Immunol. 1989; 30: 7–11PubMedSee all References, which might neutralize its biological activity. As the ability of P. aeruginosa LPS to induce IL-8 and E-selectin is CD14-mediated, antibodies to the carbohydrate region of LPS in CF sputum could neutralize proinflammatory mediator release in a manner analogous to neutralization of the inflammatory properties of LPS by antibodies to the O side chain. Further investigation into this aspect of CF biology is required.Overall, Ernst et al. have made an important contribution towards understanding the pathogenesis of P. aeruginosa in CF lung disease. The questions raised here about this work highlight the greatness of the diversity of natural phenomena acknowledged by Kepler, as all good scientific investigations raise more questions than they answer. Although the importance of Kepler’s statement is clear, one must also not forget Mark Twain’s take on scientific inquiry:"There is something fascinating about science. One gets such wholesome return of conjecture out of such a trifling investment of fact."