DNA and actin bind and inhibit interleukin-8 function in cystic fibrosis sputa - In vitro effects of mucolytics

Infection of the cystic fibrosis (CF) airways elicits an exaggerated, inter leukin-8 (IL-8) mediated, neutrophil inflammatory response. Necrosing neutr ophils release DNA and actin into the airways, increasing the viscoelastici ty of airway secretions. Mucolytics aim to improve airway clearance by redu cing this viscoelasticity. DNase I reduces the viscoelasticity of CF sputum , and a human recombinant form of this enzyme is widely administered to pat ients with CF. Gelsolin, which cleaves actin polymers, is also known to red uce CF sputum viscosity in vitro, and it has been proposed as a future muco lytic agent. We have shown that the anionic polymers DNA and actin bind and mask immunologic recognition of the basic peptide IL-8 and prevent this ch emokine from binding to neutrophil receptors. Reduction of CF sputum viscos ity by DNase I or gelsolin in vitro was demonstrated to increase the propor tion of free IL-8 and the IL-8-dependent neutrophil chemotactic activity of sputum supernatants. We hypothesize that an electrostatic interaction betw een polymer and chemokine may limit the inflammatory potential of the latte r, but that this interaction may be weakened by polymer cleavage. The poten tial risk of increased inflammation via this mechanism suggests a caveat sh ould be attendant on treatment of patients with CF with these mucolytic age nts.