Genetic and pharmacological evaluation of cathepsin s in a mouse model of asthma.
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.
Deschamps
Kathleen
K
Department of In Vivo Sciences, Central Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway Kirkland, QC, Canada, H9H 3L1.
Cromlish
Wanda
W
Weicker
Sean
S
Lamontagne
Sonia
S
Huszar
Sarah L
SL
Gauthier
Jacques Yves
JY
Mudgett
John S
JS
Guimond
Alain
A
Romand
Raymond
R
Frossard
Nelly
N
Percival
M David
MD
Slipetz
Deborah
D
Tan
Christopher M
CM
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
D010047:Ovalbumin; D002403:Cathepsins; C028217:cathepsin S