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Mast cell proteases as pharmacological targets
#MMPMID25958181
Caughey GH
Eur J Pharmacol
2016[May]; 778
(?): 44-55
PMID25958181
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Mast cells are rich in proteases, which are the major proteins of intracellular
granules and are released with histamine and heparin by activated cells. Most of
these proteases are active in the granule as well as outside of the mast cell
when secreted, and can cleave targets near degranulating mast cells and in
adjoining tissue compartments. Some proteases released from mast cells reach the
bloodstream and may have far-reaching actions. In terms of relative amounts, the
major mast cell proteases include the tryptases, chymases, cathepsin G,
carboxypeptidase A3, dipeptidylpeptidase I/cathepsin C, and cathepsins L and S.
Some mast cells also produce granzyme B, plasminogen activators, and matrix
metalloproteinases. Tryptases and chymases are almost entirely mast
cell-specific, whereas other proteases, such as cathepsins G, C, and L are
expressed by a variety of inflammatory cells. Carboxypeptidase A3 expression is a
property shared by basophils and mast cells. Other proteases, such as mastins,
are largely basophil-specific, although human basophils are protease-deficient
compared with their murine counterparts. The major classes of mast cell proteases
have been targeted for development of therapeutic inhibitors. Also, a human
?-tryptase has been proposed as a potential drug itself, to inactivate of snake
venins. Diseases linked to mast cell proteases include allergic diseases, such as
asthma, eczema, and anaphylaxis, but also include non-allergic diseases such as
inflammatory bowel disease, autoimmune arthritis, atherosclerosis, aortic
aneurysms, hypertension, myocardial infarction, heart failure, pulmonary
hypertension and scarring diseases of lungs and other organs. In some cases,
studies performed in mouse models suggest protective or homeostatic roles for
specific proteases (or groups of proteases) in infections by bacteria, worms and
other parasites, and even in allergic inflammation. At the same time, a clearer
picture has emerged of differences in the properties and patterns of expression
of proteases expressed in human mast cell subsets, and in humans versus other
mammals. These considerations are influencing prioritization of specific protease
targets for therapeutic inhibition, as well as options of pre-clinical models,
disease indications, and choice of topical versus systemic routes of inhibitor
administration.
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