title: Genetic and pharmacological evaluation of cathepsin s in a mouse model of asthma.
abstract: Cathepsin S (Cat S) is predominantly expressed in antigen-presenting cells and is up-regulated in several preclinical models of antigen-induced inflammation, suggesting a role in the allergic response. Prophylactic dosing of an irreversible Cat S inhibitor has been shown to attenuate pulmonary eosinophilia in mice, supporting the hypothesis that Cat S inhibition before the initiation of airway inflammation is beneficial in airway disease. In addition, Cat S has been shown to play a role in more distal events in the allergic response. To determine where Cat S inhibition may affect the allergic response, we used complementary genetic and pharmacological approaches to investigate the role of Cat S in the early and downstream allergic events in a murine model of antigen-induced lung inflammation. Cat S knockout mice did not develop ovalbumin-induced pulmonary inflammation, consistent with a role for Cat S in the development of the allergic response. Alternatively, wild-type mice were treated with a reversible, highly selective Cat S inhibitor in prophylactic and therapeutic dosing paradigms and assessed for changes in airway inflammation. Although both treatment paradigms resulted in potent Cat S inhibition, only prophylactic Cat S inhibitor dosing blocked lung inflammation, consistent with our findings in Cat S knockout mice. The findings indicate that although Cat S is up-regulated in allergic models, it does not appear to play a significant role in the downstream effector inflammatory phase in this model; however, our results demonstrate that Cat S inhibition in a prophylactic paradigm would ameliorate airway inflammation.
authors.affiliation: Department of In Vivo Sciences, Central Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway Kirkland, QC, Canada, H9H 3L1.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Deschamps
authors.forename: Wanda
authors.initials: W
authors.lastname: Cromlish
authors.forename: Sean
authors.initials: S
authors.lastname: Weicker
authors.forename: Sonia
authors.initials: S
authors.lastname: Lamontagne
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Huszar
authors.forename: Jacques Yves
authors.initials: JY
authors.lastname: Gauthier
authors.forename: John S
authors.initials: JS
authors.lastname: Mudgett
authors.forename: Alain
authors.initials: A
authors.lastname: Guimond
authors.forename: Raymond
authors.initials: R
authors.lastname: Romand
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Deborah
authors.initials: D
authors.lastname: Slipetz
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tan
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002403:Cathepsins / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004341:Drug Evaluation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000009:adverse effects / Q000494:pharmacology; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D010047:Ovalbumin; D002403:Cathepsins; C028217:cathepsin S