The primary function of neutrophils in the innate immune response--to contain and kill invading microbial pathogens--is achieved through a series of rapid and coordinated responses culminating in phagocytosis and intracellular killing of the pathogens. Neutrophils have a potent antimicrobial arsenal that includes oxidants, proteinases, and cationic peptides. Reactive oxygen species such as oxygen are produced by the phagocyte NADPH oxidase and are microbicidal. Granules within the neutrophil cytoplasm contain potent proteolytic enzymes and cationic proteins that can digest a variety of microbial substrates. These compounds are released directly into the phagosome, compartmentalizing both the pathogen and the cytotoxic products. Under pathological circumstances, however, unregulated release of microbicidal compounds into the extracellular space can paradoxically damage host tissues. Nonspecific inhibition of neutrophils is not clinically realistic, as it would leave the host vulnerable to infection. As the mechanisms of action of neutrophil granule contents are elucidated, therapeutic targets will be identified that will allow for suppression of neutrophils' detrimental effects while avoiding inhibition of their beneficial effects.

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Pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the basis for this susceptibility remains incompletely understood. One hypothesis is that CF airway surface liquid (ASL) is abnormal and interferes with neutrophil function. To study this possibility, we developed an in vitro system in which we collected ASL from primary cultures of normal and CF airway epithelial cells. Microbial killing was less efficient when bacteria were incubated with neutrophils in the presence of ASL from CF epithelia compared with normal ASL. Antimicrobial functions of human neutrophils were assessed in ASL from CF and normal epithelia using a combination of quantitative bacterial culture, flow cytometry, and microfluorescence imaging. The results of these assays of neutrophil function were indistinguishable in CF and normal ASL. In contrast, the direct bactericidal activity of ASL to Escherichia coli and to clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa was substantially less in CF than in normal ASL, even when highly diluted in media of identical ionic strength. Together, these observations indicate that the antimicrobial properties of ASL in CF are compromised in a manner independent of ionic strength of the ASL, and that this effect is not mediated through a direct effect of the ASL on phagocyte function.