Modulation of airway inflammation in cystic fibrosis. In vivo suppression of interleukin-8 levels on the respiratory epithelial surface by aerosolization of recombinant secretory leukoprotease inhibitor.

Abstract

Based on the knowledge that neutrophil elastase (NE) in cystic fibrosis (CF) epithelial lining fluid (ELF) can induce human bronchial epithelial cells to express the gene for interleukin 8 (IL-8), an 8.5-kD neutrophil chemoattractant, we have evaluated CF ELF for the presence of IL-8, and investigated the ability of aerosolized recombinant secretory leukoprotease inhibitor (rSLPI) to suppress NE, and hence IL-8, levels on the respiratory epithelial surface in CF. Enzyme-linked immunoassay revealed 21.9±4.8 nM IL-8 in CF ELF compared with none in normals. Active NE was detectable in ELF of all individuals with CF and was significantly decreased (P < 0.03) after aerosolization of rSLPI. Human bronchial epithelial cells exposed to CF ELF recovered before rSLPI therapy expressed IL-8 mRNA transcripts, but ELF recovered after rSLPI therapy induced far less bronchial epithelial cell IL-8 gene expression. Consistent with this, rSLPI aerosol therapy caused a marked reduction in CF ELF IL-8 levels (P < 0.05) and neutrophil number (P < 0.02). There was also a clear association between CF ELF active NE and IL-8 levels (r = 0.94). These data suggest that rSLPI therapy not only suppresses respiratory epithelial NE levels, but also breaks a cycle of inflammation on the CF epithelial surface. (J. Clin. Invest. 1992. 90:1296-1301.) Key words: aerosol therapy * antiprotease * cytokinev neutrophil chemoattractant * neutrophil elastase

DNA binds neutrophil elastase and mucus proteinase inhibitor and impairs their functional activity

“…Also, the fraction of administered MPI which reacts with DNA-bound NE will form an unstable inhibitory complex as we have shown in vitro. The effects discussed here may explain why considerably high amounts of recombinant MPI are required to observe significant NE inhibition in lung secretion of cystic fibrosis patients [4].…”

“…Cystic fibrosis is a disease whose major clinical manifestations are in the lung with accumulation of purulent mucus, bacterial infections, airway inflammation and obstruction and ultimately lung tissue destruction due to NE and other neutrophil proteinases ( [4] and refs. therein).…”

“…In cystic fibrosis airways secretions this poor affinity may, however, be largely compensated for by the enormous DNA concentration present in these fluids. Hence, it is likely that a large proportion of the MPI administered by aerosol to inhibit NE in lung secretions of cystic fibrosis patients [4] will be entrapped in insoluble DNA and will, therefore, not be available for NE inhibition. Also, the fraction of administered MPI which reacts with DNA-bound NE will form an unstable inhibitory complex as we have shown in vitro.…”

“…Despite ~:his high load of inhibitor, bronchial secretions from patients ~vith cystic fibrosis contain significant amounts of active NE [4]. On the other hand, these secretions also contain large quantities ~f neutrophil-derived DNA [5].…”

The Effect of Liposome Encapsulation on the Pharmacokinetics of Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) Therapy after Local Delivery to a Guinea Pig Asthma Model

“…rSLPI's therapeutic activity has been demonstrated previously in animal asthma models (Wright et al, 1999) and in human studies (McElvaney et al, 1993, McElvaney et al, 1992. The success of inhaled rSLPI therapy has been limited, however, by rapid clearance and extensive degradation by proteases, particularly cathepsins.…”