An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats

Lohman, Rink-Jan, Cotterell, Adam J., Barry, Grant D., Liu, Ligong, Suen, Jacky Y., Vesey, David A. and Fairlie, David P. (2012) An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. The FASEB Journal, 26 7: 2877-2887.


Author Lohman, Rink-Jan
Cotterell, Adam J.
Barry, Grant D.
Liu, Ligong
Suen, Jacky Y.
Vesey, David A.
Fairlie, David P.
Title An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats
Journal name The FASEB Journal  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2012-07
Sub-type Article
DOI 10.1096/fj.11-201004
Volume number 26
Issue number 7
ISSN 0892-6638
1530-6860
Start page 2877
End page 2887
Total pages 11
Place of publication Bethesda, MD, United States
Publisher Federation of American Societies for Experimental Biology
Collection year 2013
Language eng
Formatted abstract Multiple serine proteases exert proinflammatory actions by signaling through protease-activated receptor-2 (PAR2) on the cell surface. Although inhibitors of individual proteases are anti-inflammatory, we sought to discover whether the first potent antagonist of their common target PAR2 might be beneficial in treating chronic arthritis-like inflammatory disease. Using a fluorescence assay, a novel compound, GB88, was shown to antagonize PAR2-induced intracellular Ca2+ release in human monocyte-derived macrophages, being 1000 times more potent than a control compound, ENMD-1068 (IC50 1.6±0.5 μM vs. 1.2±0.4 mM, respectively). In Wistar rats, GB88 was orally bioavailable (F=55%, Tmax 4 h, Cmax 1.7 μM, 10 mg/kg). GB88 inhibited the acute paw edema induced in Wistar rats by intraplantar λ-carrageenan or PAR2 agonists 2-furoyl-LIGRLO-NH2 or mast cell β-tryptase, without inhibiting proteolytic activity of tryptase in vitro. In the chronic collagen-induced model of arthritis in rats, GB88 (10 mg/kg) was disease modifying and ameliorated pathological and histopathological changes (edema, pannus formation, synovial hyperplasia, collagen degradation, macrophage invasion, mast cell degranulation) compared to untreated arthritic controls. The results suggest that an orally active PAR2 antagonist is effective in treating chronic arthritis in rats through inhibiting macrophage infiltration, mast cell degranulation, and β-tryptase-PAR2 signaling in joint inflammation.—Lohman, R.-J., Cotterell, A. J., Barry, G. D., Liu, L., Suen, J. Y., Vesey, D. A., Fairlie, D. P. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats.
Keyword Joint inflammation
Beta-tryptase
In-Vivo
Inflammatory arthritis
Rheumatoid-arthritis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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