title: Secretory leukocyte protease inhibitor prevents allergen-induced pulmonary responses in animal models of asthma.
abstract: Secretory leukocyte protease inhibitor (SLPI) is a naturally occurring protein of human airways that exhibits broad spectrum inhibitory activity against mast cell and leukocyte serine proteases implicated in asthma pathology. To assess the potential therapeutic utility of SLPI in this disorder, its effects on antigen-induced pulmonary responses were evaluated. In Ascaris-sensitized sheep, SLPI (3 mg) administered by aerosol daily for 4 days, with the final dose 0.5 h before antigen challenge, reduced the areas under the curve for early- and late-phase bronchoconstriction (73 and 95%, respectively; p <.05 versus control responses). SLPI also inhibited the development of airway hyperresponsiveness to carbachol (84%, p <. 05 versus control response) measured 24 h after antigen challenge. In ovalbumin-sensitized guinea pigs, intratracheal administration of SLPI daily for 3 days, with the final dose 1 h before antigen challenge, inhibited the development of airway hyperresponsiveness to histamine with an ED50 of <0.05 mg/kg. Prolonged pharmacodynamic activity of SLPI was observed in both species. In a murine model of atopic asthma, SLPI inhibited leukocyte influx into the airways after chronic allergen challenge. SLPI administered to sheep by the predosing protocol described above also prevented the antigen-induced decrease of tracheal mucus velocity (p <.05). In addition, a single aerosol administration of SLPI (30 mg) to sheep 1 h after antigen challenge inhibited the subsequent late-phase bronchoconstriction and development of hyperresponsiveness and reversed the stimulated decrease in tracheal mucus velocity. These results suggest that SLPI may provide therapeutic intervention against the pathophysiology of asthma and its underlying pathology.
authors.affiliation: Department of Inflammation Research, Amgen, Inc., Boulder, Colorado, USA. cwright@amgen.com
authors.forename: C D
authors.initials: CD
authors.lastname: Wright
authors.forename: A M
authors.initials: AM
authors.lastname: Havill
authors.forename: S C
authors.initials: SC
authors.lastname: Middleton
authors.forename: M A
authors.initials: MA
authors.lastname: Kashem
authors.forename: P A
authors.initials: PA
authors.lastname: Lee
authors.forename: D J
authors.initials: DJ
authors.lastname: Dripps
authors.forename: T G
authors.initials: TG
authors.lastname: O'Riordan
authors.forename: M P
authors.initials: MP
authors.lastname: Bevilacqua
authors.forename: W M
authors.initials: WM
authors.lastname: Abraham
mesh_terms: D000336:Aerosols; D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012756:Sheep; D014132:Trachea / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D000336:Aerosols; D000485:Allergens; D018927:Anti-Asthmatic Agents; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; C506815:Slpi protein, mouse