Mast cells derive from the bone marrow and migrate into connective and mucosal tissues (Galli, 1993), where they are located at strategic points around capillaries close to nerve endings (Theoharides, 1996). Mast cells are critical for allergic reactions where the stimulus is immunoglobulin E (IgE) and speci®c antigen; however, there are also other nonimmune mast cell triggers that include anaphylatoxins, kinins, cytokines, as well as various neuropeptides (Baxter & Adamik, 1978; Coey, 1973) such as somatostatin (Theoharides & Douglas, 1978), neurotensin (NT) (Carraway et al., 1982) and substance P (SP) (Fewtrell et al., 1982). When stimulated, mast cells synthesize and secrete numerous vasoactive, nociceptive and in¯amma- tory mediators (Galli, 1993) that include histamine, kinins, prostaglandins, leukotrienes, cytokines, as well as the proteo- lytic enzymes chymase and tryptase (Schwartz, 1987). Such evidence has implicated mast cells also in in¯ammatory conditions (Galli, 1993; Theoharides, 1996). Sulphated pro- teoglycans constitute the major constituents of mast cell secretory granules. Of these, heparin is mostly found in connective tissue mast cells (CTMC), while chondroitin sulphate in MMC (Seldin et al., 1985b; Razin et al., 1983). Recent evidence indicates that chondroitin sulphate is also present in human connective tissue (Krilis et al., 1992) and umbilical cord-derived human mast cells (Blom et al., 1996). A number of compounds have been reported to block rat mast cell secretion experimentally. These include the lodox- omides (Johnson, 1980), doxantrazole (Pearce et al., 1982; Fox et al., 1988), quercetin (Fox et al., 1988; Fewtrell & Gomperts, 1977) and certain histamine-1 receptor antagonists such as hydroxyzine (Theoharides et al., 1985; Fischer et al., 1995) and ketotifen (Nemeth et al., 1987). The only clinically available `anti-allergic’ drugs are cromolyn (Orr et al., 1971) and its structurally related nedocromil (EnerbaÈ ck & Berg- stroÈ m, 1989); yet, they are not capable of eectively blocking human mast cell secretion (Okayama et al., 1992). In addition, the inhibitory action of these drugs is short-lived due to the induction of tachyphylaxis (Theoharides et al., 1980) and they do not inhibit mucosal mast cells (MMC) (Barrett & Metcalfe, 1985; Pearce et al., 1982; Fox et al., 1988). Among mast cell derived molecules, histamine has an autoinhibitory action only in the brain through activation of histamine-3 receptors (Rozniecki et al., 1999), while arachi- donic acid products have variable and weak inhibitory eects (Theoharides, 1990). We hypothesized that chondroitin sulphate released from in¯amed tissue, as well as from mast cells, could have an inhibitory eect on mast cell secretion. Here we show that chondroitin sulphate is a potent inhibitor of histamine release from CTMC.
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