Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixteen patients with allergic rhinitis were recruited into a double-blind crossover protocol studying the immediate effect of nedocromil sodium (NS) on the pattern of nasal symptoms and secretions after allergen challenge. After pretreatment with placebo or NS, allergen challenge resulted in pruritus, rhinorrhea, nasal congestion, and/or sneezing within 10 minutes in 12 of 16 subjects. Prostaglandin D2 (PGD2), a marker of mast cell degranulation, increased proportionately with symptom scores, remaining above the 95% confidence interval for 120 minutes after both pretreatments. No difference in PGD2 between the NS-treatment and placebo-treatment days was observed. Protein markers extravasated through the vasculature (albumin and IgG) or secreted by mucosal glands (lactoferrin) were assayed. Total protein, albumin, IgG, and lactoferrin all remained greater than 95% confidence interval for 100 minutes after allergen challenge in the placebo-pretreated group and 120 minutes in the NS-pretreated group. Although there appeared to be a trend for lower secretion of PGD2, albumin, and IgG in the NS-treated group, the overall differences did not achieve statistical significance. This protocol revealed that two topical 130 microliter doses of a 1% solution of NS failed to significantly reduce allergen-induced symptoms, PGD2 generation, or secretion of albumin, IgG, or lactoferrin when NS was compared with placebo. The anti-inflammatory and mast cell-stabilizing effects of NS may require more prolonged pretreatment before provocation to be effective.
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PMID:Effects of nedocromil sodium on allergen-induced rhinitis in humans. 131 Oct 8

Our previous skin chamber studies have shown prominent accumulation of viable neutrophils in human allergic skin reaction sites. To determine whether such neutrophils release components that may be pathogenic in allergic reactions, we have compared the patterns of release of five components: 1) lactoferrin, present in specific granules; 2) and 3) elastase and myeloperoxidase, present mainly in azurophilic granules; 4) lactic dehydrogenase, a cytosolic component generally released during cell damage; 5) histamine, present in mast cells and basophils but not in neutrophils. In 13 pollen-sensitive subjects we found that continuous antigen challenge for 5 h lead to a peak of histamine release into overlying skin chambers during the 1st h, followed by a plateau of low level histamine release over the succeeding 4 h. In contrast, there was no significantly increased released of lactoferrin or elastase during the first h, but significantly increased accumulation of these components at Ag challenge sites over the next 4 h. There was no significant difference at Ag vs buffer control sites in the levels of either myeloperoxidase or lactic dehydrogenase. The increased levels of lactoferrin and elastase at antigen challenge sites in the 2nd to 5th h were not simply a reflection of the greater numbers of neutrophils present in such sites because the levels of these components did not correlate significantly with the number of neutrophils in chamber fluids obtained from individual sites. However, such lactoferrin levels did correlate significantly with the amount of histamine released earlier during the 1st h of Ag challenge at individual sites. These findings suggest a selective in vivo release of neutrophil components in IgE-mediated human allergic skin reactions, possibly related in degree to earlier mast cell activation. Inasmuch as lactoferrin likely plays a role in reactive oxidants effects and elastase is a potent nonspecific protease, release of these agents could play a pathogenic role in late phase allergic reactions.
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PMID:Release of lactoferrin and elastase in human allergic skin reactions. 169 68

Allergic rhinitis is characterized by a profuse rhinorrhea in addition to paroxysms of sneezing, nasal congestion, and pruritus. To define better the sources of nasal secretion produced during rhinitis, nasal allergen challenges were performed on nine atopic subjects with seasonal rhinitis. A single dose of allergen was sprayed into one side of the nose, and nasal lavages were collected bilaterally for 7 hours. Nasal lavages were assayed for protein (total protein, albumin, lactoferrin, and lysozyme) and mediator (histamine and prostaglandin D2) content. Protein concentrations increased and remained elevated above baseline levels in both ipsilateral and contralateral secretions for up to 3 hours after allergen challenge. The proportion of albumin relative to total protein (the albumin percent) increased on the ipsilateral side, whereas the relative proportions of lactoferrin and lysozyme (the lactoferrin percent and lysozyme percent) increased on the contralateral side. Prostaglandin D2, but not histamine, increased selectively on the ipsilateral side. These data suggest that the ipsilateral protein secretory response is due to allergen-induced mast cell mediator release causing increased vascular permeability, whereas the contralateral protein secretory response is primarily a reflex-induced glandular secretion.
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PMID:The pathophysiology of rhinitis. V. Sources of protein in allergen-induced nasal secretions. 171 3

Whether the origin of the progenitor of mast cells occurs in the basophil/mast cell system or the myeloid cell system of neutrophils and monocytes/macrophages remains controversial. Lactoferrin or lysozyme is known to be present in the myeloid cell system. By electron microscopy, antibodies against lactoferrin and lysozyme were observed to stain the granules of normal bone marrow mast cells. This supports the proposal that the precursor cell of bone marrow mast cells is nearer to the myeloid cell system than the basophil/mast cell system.
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PMID:Ultrastructural evidence for the origin of mast cells in normal human bone marrow. 171 51

Normally the daily volume of lower respiratory tract secretions, in man, is probably less than 100 ml. In hypersecretory disease the volume increases sufficiently to cause cough and expectoration of secretions as sputum. The proportions which are sol or gel vary in disease as does the way in which constituent molecules partition in each phase. The constituent molecules and the cells which produce them (indicated in parentheses) may be classified as follows: 1. Mucus-glycoproteins present as droplets, or sheets (produced by mucous cells), periciliary fluid (serous or ciliated cell or a transudate), surface muco-substance (all epithelial cells) or surfactant hypophase (Clara or type II alveolar cells). 2. Proteins and peptides such as lysozyme (serous cell and macrophage), lactoferrin (serous cell and neutrophil), secretory piece (surface epithelium and submucosal glands), regulatory neuropeptides (dense-core granulated cell and both motor and sensory nerves) and fibronectin (alveolar macrophages). 3. Glycosaminoglycans such as heparan sulphate (epithelial membranes), heparin (mast cell), chondroitin sulphates and hyaluronate (connective tissue constituents). 4. Lipids including triglycerides (stored in cells) glycolipids (cell membrane), phospholipids (type II alveolar cells), sphingolipids (cell membrane), steroids (? Clara cells) and terpenes (cell membrane). 5. Anti-proteases and anti-oxidants such as bronchial protease inhibitors (serous anc Clara cells), alpha-2-macroglobulin (macrophage), alpha-1-antitrypsin (transudate) and anti-oxidants (type II alveolar cell and macrophage). 6. Other 'secretions' including ions and water (surface epithelium and submucosal glands), mediators of inflammation (migratory cell granules and their membranes), and serum proteins (present in transudate/exudate).
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PMID:The origins of secretions in the lower respiratory tract. 332 67

To compare cellular and mediator responses in early developing late-phase skin reactions (LPR) and delayed-hypersensitivity (DH) reactions in the same subjects, responses in skin chambers overlying sites of challenge with pollen antigen and Candida albicans antigens were compared in six humans with demonstrated prominent LPR and DH responses. Histamine levels in overlying chamber fluids at 1 h were much higher at LPR than at DH sites (P = 0.002). After the next 4 h, leukocyte exudation was higher at LPR than at DH sites (P = 0.005). Most leukocytes were activated neutrophils with greater frequency of superoxide-secreting cells and released lactoferrin at LPR than at DH sites (P = 0.01 and P = 0.02, respectively). The frequency of exuding eosinophils was higher, but not significantly so (P = 0.5), at LPR sites. Although significantly more eosinophils at LPR sites were activated (P = 0.02), the levels of released eosinophilic cationic protein were not significantly higher at LPR sites (P = 0.09). The levels of interleukin-8 (IL-8), but not IL-6, were greater at LPR than at DH sites. During the first 5 h of challenge there was greater mast cell activation and subsequent exudation of activated neutrophils at sites of developing LPR than at DH sites, possibly related to greater local IL-8 levels. The frequency of activated eosinophils was also greater at LPR sites. These different initial inflammatory responses could play a role in determining expression of LPR or DH reactions.
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PMID:Comparison of inflammatory events during developing immunoglobulin E-mediated late-phase reactions and delayed-hypersensitivity reactions. 966 69

Human tryptase is a structurally unique and mast cell specific trypsin-like serine protease. Recent biological and immunological investigations have implicated tryptase as a mediator in the pathology of numerous allergic and inflammatory conditions including rhinitis, conjunctivitis, and most notably asthma. A growing body of data further implicates tryptase in certain gastrointestinal, dermatological, and cardiovascular disorders as well. The recent availability of potent, and selective tryptase inhibitors, though, has facilitated the validation of this protease as an important therapeutic target as well. Herein, we describe the design and potency of four classes of selective tryptase inhibitors, of which the first three types are synthetic and the fourth is natural in origin: 1) peptidic inhibitors (e.g., APC-366), 2) dibasic inhibitors (i.e., pentamidine-like), 3) Zn(2+)-mediated inhibitors (i.e., BABIM-like), and 4) heparin antagonists (e.g., lactoferrin). These inhibitors have been tested in the airways and skin of allergic sheep. Aerosol administration of tryptase inhibitors from each structural class 30 minutes before, and 4 hours and 24 hours after allergen challenge, abolishes late phase bronchoconstriction and airway hyperresponsiveness in a dose-dependent manner. Moreover, intradermal injection of APC-366 blocks the cutaneous response to antigen. These studies provide the essential proof-of-concept for the further pursuit of tryptase inhibitors for the treatment of asthma, and perhaps other allergic diseases. Results from clinical studies with the first generation tryptase inhibitor APC-366, currently in phase II trials for the treatment of asthma, provide additional support for a pathological role for tryptase in this disease. Notable advances in the area of tryptase inhibitor design at Axys Pharmaceuticals, Inc. include a novel, zinc-mediated, serine protease inhibitor technology (described herein), and the discovery of a unique class of extremely potent and selective dibasic tryptase inhibitors. Independently, an X-ray crystal structure of active tryptase tetramer complexed with 4-amidinophenyl pyruvic acid has been reported. It is anticipated that these discoveries will further accelerate the design of structurally novel tryptase inhibitors as well as the development of new drugs for the treatment of mast cell tryptase-mediated disorders.
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PMID:Inhibitors of tryptase for the treatment of mast cell-mediated diseases. 1019 50

Inhibitors of mast cell tryptase and chymase can be effective as mast cell stabilising compounds. Lactoferrin has been reported to inhibit tryptase activity, but its actions on other serine proteases of mast cells and its potential to alter mast cell function are not known. We have examined the ability of lactoferrin to inhibit mast cell tryptase, chymase and cathepsin G, and investigated its potential to modulate the activation of human mast cells. Enzymatically dispersed cells from human skin, lung and tonsil were challenged with anti-IgE or calcium ionophore A23187, following incubation with recombinant human lactoferrin, and histamine release determined. IgE-dependent histamine release from skin mast cells was inhibited by up to 50% following incubation with lactoferrin (50 or 500 nM). Tonsil mast cells were also stabilised by lactoferrin, but not those from lung. Calcium ionophore A23187-induced histamine release was not altered by lactoferrin. A double-labelling immunocytochemical procedure revealed the presence of lactoferrin in 4-6% of mast cells, and this proportion increased to 40% following incubation with lactoferrin. Lactoferrin did not inhibit cleavage of synthetic substrates by tryptase and chymase directly, though it was able to diminish the ability of heparin to stabilise tryptase. Cathepsin G activity was inhibited by lactoferrin. The ability of lactoferrin to inhibit IgE-dependent activation of human mast cells and modulate protease activity suggests that the release of this neutrophil product may have a role in the downregulation of allergic inflammation.
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PMID:The inhibition of mast cell activation by neutrophil lactoferrin: uptake by mast cells and interaction with tryptase, chymase and cathepsin G. 1262 33

Lactoferrin (LF), a glycogen of the transferrin family with anti-bacterial and immunomodulatory properties, is expressed in various secretions and tissues. Cutaneous LF serves as a mast cell stabilising compound, modulates T cell activity and is found during IgE-mediated late phase reactions at allergen challenged sites. Culicoides hypersensitivity (CHS) in horses is a common IgE-mediated allergic dermatitis, characterised by an early and late phase cutaneous reaction upon allergen challenge. The aim of the study presented here was to examine whether LF mRNA expression in skin biopsies from horses affected by CHS prior to and 4h following intradermal challenge with a commercial C. nubeculosus extract is modified in comparison to skin biopsies from non-affected horses. In order to obtain reliable data, real time PCR was performed and genes of interest were normalized using three different housekeeping genes, beta-actin, GAPDH, beta-2-microglobulin. In comparison to non-affected horses, higher variation in LF mRNA levels both prior to and post-intradermal challenge with C. nubeculosus extract was seen in horses affected by CHS. However, the statistical analysis demonstrated that LF mRNA expression was not significantly different between CHS affected and non-affected horses prior to intradermal challenge with C. nubeculosus extract. Intradermal injection of C. nubeculosus extract did not result in local upregulation of LF mRNA at 4h post-injection. LF mRNA expression was therefore not significantly different pre- or post-intradermal challenge with C. nubeculosus extract in either group. Our data indicate that clinically normal skin of horses affected by CHS is not characterized by modified maintenance levels of LF mRNA. In contrast to human skin allergen challenged sites, LF mRNA levels in horses affected by CHS are not significantly different to that of control sites at 4h post-injection of C. nubeculosus extract.
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PMID:Lactoferrin, a glycoprotein with immunomodulatory and mast cell stabilising properties, in skin of horses suffering from Culicoides hypersensitivity. 1722 35

Pain intensity in chronic venous disease varies with the stage in the clinical-etiologic-anatomic-pathophysiologic (CEAP) classification but also with patient perception, pain being by definition subjective. The venous hypertension responsible for the varicose veins and trophic changes in CVD has a variety of algogenic repercussions in which leukocytes play a particular role, notably through their ability to roll along the vessel wall. Shear stress, hypoxia and stasis activate the marginated leukocytes to shed L-selectin from their surface and express integrins, matrix metalloproteinase 9, elastase, lactoferrin and free radicals. Meanwhile the endothelium expresses adhesion molecules that permit slow rolling on E-selectin followed by adhesion and tissue transmigration. Vein wall and valve areas in particular attract mast cells, monocyte-macrophages and T lymphocytes, and undergo remodeling. Sympathetic sensory C and Adelta fibers, which wrap around cutaneous venules and are also present in the venous intima and media, are nociceptors sensitive to the pain mediators concentrated within leukocytes, such as mast cell bradykinin, responsible for visceral pain. Neuronal inflammation combined with wall remodeling intensifies symptoms. Yet no direct link has so far been shown between pain and mast cell mediator levels. Leukocyte adhesion is also associated with the increased capillary permeability that leads to edema. Antileukocyte therapies include postural rest and venotonics which alone or in combination with compression have been shown to unstick and inhibit leukocytes. The micronized purified flavonoid fraction (MPFF) protects vascular endothelium against hypoxia and reduces adhesion molecule expression. Unlike other antileukocyte therapies, venotonics do not cause neutropenia.
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PMID:Leukocyte involvement in the signs and symptoms of chronic venous disease. Perspectives for therapy. 1772 58


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