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,
Departments of
*
Medicine,
Pathology, and
Pathobiology, University of Washington, Seattle, WA 98195;
Pacific Northwest Research Institute, Seattle, WA 98122;
¶ Molecumetics Ltd., Bellevue, WA 98005; and
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ChoongWae Pharma Corp., Seoul, Korea
Release of human lung mast cell tryptase may be important in the
pathophysiology of asthma. We examined the effect of the reversible,
nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and
hyper-reactivity in a murine model of asthma. MOL 6131 is a potent
selective nonpeptide inhibitor of human lung mast cell tryptase based
upon a 
-strand template (Ki = 45
nM) that does not inhibit trypsin (Ki
= 1,061 nM), thrombin (Ki = 23, 640
nM), or other serine proteases. BALB/c mice after i.p. OVA
sensitization (day 0) were challenged intratracheally with OVA on days
8, 15, 18, and 21. MOL 6131, administered days 18–21, blocked the
airway inflammatory response to OVA assessed 24 h after the last
OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater
anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL
6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar
lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia,
mucus secretion, and peribronchial edema and also inhibited the release
of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase
inhibition did not alter airway hyper-reactivity to methacholine in
vivo. These results support tryptase as a therapeutic target in asthma
and indicate that selective tryptase inhibitors can reduce allergic
airway inflammation.
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