Recombinant secretory leukoprotease inhibitor (rSLPI), a recombinant form of a natural airway inhibitor of neutrophil elastase (NE), is a potential therapeutic agent for cystic fibrosis (CF), a condition characterized by airway derangement mediated in part by the large burden of NE on the CF respiratory epithelial surface. After in vitro studies that demonstrated that aerosolized rSLPI retains its form and function, rSLPI was administered via aerosol to normal individuals and individuals with CF to determine the pharmacokinetics of in vivo rSLPI augmentation of the anti-NE defenses of the respiratory epithelial surface. After rSLPI aerosolization to normal individuals (100 mg single dose or 100 mg twice daily for 1 wk) there was a marked increase in SLPI levels and anti-NE capacity in airway epithelial lining fluid (ELF) at 1 h, diminishing gradually over 4 to 12 h. Interestingly, the ELF SLPI levels and anti-NE capacity achieved 12 h after 1 wk of rSLPI aerosols were no different than those 12 h after a single dose of rSLPI, suggesting that rSLPI does not accumulate on the respiratory epithelial surface after aerosolization. The ability of rSLPI to suppress NE in vivo was evaluated by aerosolization of rSLPI to individuals with CF, first as an escalating dose to assess safety, and then at doses of 100 mg twice daily for 1 wk or 50 mg twice daily for 2 wk. Before aerosol, SLPI levels in ELF of individuals with CF were the same as in normal individuals, but unlike normal individuals, individuals with CF had active NE in ELF (12.4 ± 3.0 μM) indicating that the SLPI in CF ELF was inactive. After aerosolization of 100 mg rSLPI twice daily for 1 wk there was a reduction in ELF active NE. In contrast, ELF active NE levels were not reduced with 50 mg twice daily, likely due to the failure of this dose regime to sufficiently elevate ELF SLPI levels. These data show that rSLPI is functional after both in vitro and in vivo aerosolization and can significantly suppress the NE burden in the CF lung but must be given regularly and in sufficient quantity to be effective.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine