Abstract
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 beta-strand template (K(i) = 45 nM) that does not inhibit trypsin (K(i) = 1,061 nM), thrombin (K(i) = 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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Asthma / drug therapy
-
Bridged Bicyclo Compounds, Heterocyclic / chemistry
-
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
-
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
-
Bronchial Diseases / drug therapy*
-
Bronchial Diseases / immunology
-
Bronchial Diseases / pathology
-
Bronchial Hyperreactivity / drug therapy
-
Bronchoalveolar Lavage Fluid / immunology
-
Cell Movement
-
Cytokines / biosynthesis
-
Eosinophils / immunology
-
Humans
-
Inflammation / drug therapy
-
Inflammation / immunology
-
Inflammation / pathology
-
Lung / immunology
-
Lung / metabolism
-
Lung / pathology
-
Mice
-
Mice, Inbred BALB C
-
Models, Molecular
-
Mucus / metabolism
-
Ovalbumin / immunology
-
Piperidines / chemistry
-
Piperidines / pharmacology
-
Piperidines / therapeutic use*
-
Pulmonary Edema / drug therapy
-
Pulmonary Edema / pathology
-
Pulmonary Eosinophilia / drug therapy
-
Serine Endopeptidases / metabolism*
-
Serine Proteinase Inhibitors / chemistry
-
Serine Proteinase Inhibitors / pharmacology
-
Serine Proteinase Inhibitors / therapeutic use*
-
Tryptases
-
Vascular Cell Adhesion Molecule-1 / metabolism
Substances
-
Bridged Bicyclo Compounds, Heterocyclic
-
Cytokines
-
MOL 6131
-
Piperidines
-
Serine Proteinase Inhibitors
-
Tpsb2 protein, mouse
-
Vascular Cell Adhesion Molecule-1
-
Ovalbumin
-
Serine Endopeptidases
-
Tpsab1 protein, mouse
-
Tryptases