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Biomedical subjects

M K Church

Publications and source records attributed to M K Church.

At least 109 records · Page 6Linked to original sources
PubMed1992

Endothelin-1 induces a histamine-dependent flare in vivo, but does not activate human skin mast cells in vitro.

The role of the mast cell in endothelin-1 induced flare has been investigated by in vivo and in vitro experiments. The intradermal injection of endothelin-1 (10 pmol) into human skin induced a pallor with surrounding axon-reflex flare which is similar to the flare response to histamine (1 nmol). At these doses, chosen to give identical flare areas, blood flow was increased in the area of the endothelin-induced flare over a longer period. A systemic H1-receptor antagonist significantly inhibited the area of both flares, although blood flow in the remaining portion of the endothelin-induced flare remained raised. Endothelin-1 at concentrations up to 3 x 10(-5) M failed to release histamine from human dispersed skin mast cells. We suggest from these results that a major component of endothelin-1 induced flare results from mast cell activation that is secondary to direct stimulation of sensory nerves by the peptide.

Adult↗
PubMed1992

The influence of terfenadine and ipratropium bromide alone and in combination on bradykinin-induced nasal symptoms and plasma protein leakage.

Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To assess the relevance of histamine release from metachromatic cells and the activation of cholinergic pathways, we investigated the effects of terfenadine, a histamine H1-receptor antagonist, and ipratroprium bromide, a selective antimuscarinic agent, on bradykinin induced rhinorrhoea, nasal airways resistance (NAR), nasal pain and plasma protein leakage. Oral terfenadine (120 mg) or matched placebo and nasal ipratropium bromide (80 micrograms) or matched placebo were administered at 4 hr and 30 min respectively prior to bradykinin nasal challenge in two randomized, double-blind and cross-over studies on eight non-rhinitic subjects. Thus subjects received either double-placebo, oral terfenadine and nasal placebo, oral placebo and nasal ipratopium bromide or oral terfenadine and nasal ipratropium bromide, as pretreatment. Bradykinin challenge induced mean maximal increases of 57%, 59%, 77% and 72% in NAR on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratropium bromide pretreatment days respectively. These increments were not significantly different. Similarly rhinorrhoea and nasal pain induced by bradykinin nasal challenge were not significantly different on the four challenge days. Bradykinin nasal challenge caused a mean maximal increase in albumin levels in recovered nasal lavages of 11.5, 13.0, 12.2 and 12.3 times of baseline levels on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratroprium bromide pretreatment days respectively. Similarly total protein levels achieved a mean maximal increase of 8.0, 8.2, 7.9 and 8.8 times of baseline levels on these challenge days. The increments in both albumin and total protein did not significantly differ on the 4 challenge days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine.

We have studied an aspect of the functional heterogeneity of human mast cells, namely responsiveness to the inhibitory effects of sodium cromoglycate and nedocromil sodium. The effects of these drugs were examined on the release of histamine and PGD2 from mast cells of human skin, lung, tonsils, adenoids and intestine. A high concentration, 1000 microM, of sodium cromoglycate was required to significantly inhibit histamine release from lung and tonsillar mast cells. Nedocromil sodium, 1000 microM, was more effective than sodium cromoglycate against histamine release from lung, tonsillar and adenoidal cells. Both compounds showed tachyphylaxis in lung and tonsillar mast cells but not in adenoidal and intestinal mast cells. In contrast, in intestinal mast cells, the effect of nedocromil sodium was weaker and more variable than sodium cromoglycate. Skin mast cells differed from mast cells of the other anatomical sites in being unresponsive to sodium cromoglycate and nedocromil sodium. Our results confirm that high concentrations of sodium cromoglycate and nedocromil sodium are required to achieve even modest inhibition of mediator release from human mast cells under in vitro conditions. Notwithstanding this, the results also indicate that differences exist among skin, lung, tonsillar, adenoidal and intestinal mast cells with respect to their sensitivity to sodium cromoglycate and nedocromil sodium, thus extending our knowledge of functional heterogeneity within the human mast cell populations.

Adenoids↗
PubMed1992

Nasal effects of bradykinin and capsaicin: influence on plasma protein leakage and role of sensory neurons.

Nasal insufflation with bradykinin induces nasal discomfort, rhinorrhea, and nasal blockage, all features of rhinitis. We recently showed these effects to be mediated by the B2-receptor subtype, which has been identified at neural and vascular sites. To investigate the relative contribution of capsaicin-sensitive sensory neural stimulation to the action(s) of bradykinin, two randomized double-blind placebo-controlled studies have been undertaken comparing the nasal effects of single-dose administrations of bradykinin (1.88 x 10(-3) M) and capsaicin (3.28 x 10(-5) M). In comparison with placebo, both bradykinin and capsaicin induced nasal pain/discomfort (P less than 0.01) and rhinorrhea (P less than 0.02). Bradykinin significantly increased nasal airways resistance (P less than 0.005) and plasma protein exudation (P less than 0.02). No such changes were identified after nasal challenge with capsaicin. These findings suggest that bradykinin-induced nasal discomfort and rhinorrhea are neurally mediated, whereas the effects on nasal airways resistance and plasma protein exudation are due to a direct vascular action. In addition, these findings question the role of capsaicin-sensitive sensory neurons in nasal vasculature responses, because no vascular effects of capsaicin could be identified in the human nasal mucosa.

Adult↗
PubMed1992

Comparison of the modulatory effect of ketotifen, sodium cromoglycate, procaterol and salbutamol in human skin, lung and tonsil mast cells.

To assess the influence of mast cell heterogeneity on the inhibition of mediator release by drugs, the effects of ketotifen, sodium cromoglycate and beta-adrenoceptor agonists were examined against IgE-dependent histamine and prostaglandin D2 release from enzymatically dispersed human skin, lung and tonsillar mast cells. At high concentrations, ketotifen was an inhibitor of histamine and prostaglandin D2 release from lung and tonsillar mast cells. No cross-tachyphylaxis with sodium cromoglycate was seen. In skin mast cells no inhibition of mediator release was observed with 1.0 microM ketotifen, above which histamine release was induced. Sodium cromoglycate was a weak inhibitor of histamine and prostaglandin D2 release from lung and tonsillar mast cells and showed tachyphylaxis. Sodium cromoglycate did not inhibit histamine and prostaglandin D2 release from skin mast cells. On the other hand, no heterogeneity was observed with the beta-adrenoceptor agonists, procaterol and salbutamol. beta-Adrenoceptor stimulants were significantly more effective in inhibiting prostaglandin D2 than histamine release. No tachyphylaxis was seen with prolongation of the incubation time before challenge. Our results suggest that human mast cells are heterogeneous with respect to the modulation of mediator release by ketotifen and sodium cromoglycate but not beta-adrenoceptor agonists.

Albuterol↗
PubMed1992

Density profile of bronchoalveolar lavage eosinophils in the guinea pig model of allergen-induced late-phase allergic responses.

Inhalation of aerosolized ovalbumin by guinea pigs both during sensitization and upon challenge induces a pulmonary eosinophilia as assessed by cells recovered in bronchoalveolar lavage fluid (BALF). In comparison with BALF eosinophil numbers in naive animals of 0.82 +/- 0.2 x 10(6) cells, those in sensitized animals before challenge and 17 and 72 h after challenge were 1.48 +/- 0.2 x 10(6), 2.60 +/- 0.6 x 10(6), and 4.2 +/- 0.7 x 10(6) cells, respectively. BALF eosinophils from all these groups were notable for their heterogeneity with respect to density, size, and appearance under the electron microscope. In comparison with peritoneal eosinophils, which had a single mean density peak of 1.088 +/- 0.001 g/ml, BALF cells comprised hypodense (less than 1.080 g/ml), normodense (1.080 to 1.096 g/ml), and hyperdense (greater than 1.096 g/ml) eosinophils. The percentage of hypodense eosinophils rose from 25% in naive animals to 63% in sensitized animals (P less than 0.001) and fell after challenge. In contrast, challenge induced the appearance of hyperdense eosinophils, which rose from 6% in sensitized animals to 42% 72 h after challenge (P less than 0.001). Blood eosinophils in naive animals showed a similar profile to those in the lung, but after sensitization and challenge no gross changes in the proportion of either hypodense or hyperdense eosinophils were observed. Flow cytometric analysis of BALF eosinophils indicated that hypodense eosinophils, with a mean diameter of 15.8 microns, were larger than both normodense and hyperdense eosinophils, which had mean diameters of 14.3 and 11.6 microns, respectively. Although the numbers and size of granules were not reduced in hypodense BAL eosinophils, electron microscopy morphology indicated a reduced granular content.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergens↗
PubMed1992

Kallikrein-like activity in the bronchoalveolar lavage (BAL) fluid of sensitized, challenged guinea-pigs.

Sensitization and challenge of guinea-pig airways with aerosols of ovalbumin solution administered through an endotracheal tube leads to a significant increase in kallikrein-like enzyme activity in bronchoalveolar lavage (BAL) fluid. This increase is present up to six hours after challenge and may be related to changes in airways resistance that persist for similar periods.

Aerosols↗
PubMed1992

Repeated inhalation of bradykinin attenuates adenosine 5'-monophosphate (AMP) induced bronchoconstriction in asthmatic airways.

Repeated bronchial challenges with inhaled bradykinin lead to a rapid loss of the bronchoconstrictor response and this has been suggested to be due to depletion of contractile neuropeptides from sensory nerve endings. If adenosine 5'-monophosphate (AMP), another potent bronchoprovocant in asthma, and bradykinin share a common pathway in inducing bronchoconstriction in asthmatic subjects, then repeated bradykinin bronchoprovocation tests should reduce the response to subsequent inhalation of AMP. We examined this hypothesis in eight asthmatic subjects in a double-blind, randomized study. On the histamine study day, two consecutive concentration-response studies with inhaled histamine were followed by a third consecutive challenge with AMP and the provocation concentration producing a 20% fall in forced expiratory volume in one second from the post-diluent baseline value (PC20 FEV1) for this agonist was calculated. On the bradykinin study day, two consecutive bronchoprovocation tests with bradykinin were followed by a third inhalation challenge to obtain the PC20AMP value. On a further occasion, the asthmatic subjects underwent two consecutive concentration-response studies with inhaled bradykinin followed by a third consecutive challenge with histamine. On the histamine study day, the geometric mean PC20AMP value was 28.1 mg.ml-1, whilst on the bradykinin study day, the fifteenfold reduction in bradykinin responsiveness after the second bradykinin challenge was accompanied by a significant reduction of the airway responsiveness to AMP, the PC20AMP being 59.8 mg.ml-1. A similar reduction in bradykinin responsiveness failed to alter the airway response to a subsequent inhalation with histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1991

Inflammatory mediators and cellular infiltration of the lungs in a guinea pig model of the late asthmatic reaction.

Alterations in cell numbers, vascular permeability, and concentrations of various inflammatory mediators in the lung were measured in a guinea pig model of the late asthmatic reaction. Animals sensitized by inhalation of ovalbumin were challenged with an aerosol of ovalbumin or saline, and bronchoalveolar lavage fluid (BALF) and peripheral blood were collected after periods ranging from 5 min to 72 h. Increased vascular leakage within the lungs was indicated by elevated BALF/plasma albumin ratios at all time points, and was maximal 6 h after challenge. There were increased numbers of eosinophils in BALF by 6 h after challenge and they remained elevated at least until 72 h. A corresponding increase in the proportion of blood leukocytes represented by eosinophils was observed at 6 and 17 h, which suggests that these cells may be drawn to the lung following their release into the circulation, but by 72 h the proportion in blood had returned to normal. A transitory neutrophilia was evident in BALF and blood 6 h after allergen exposure, but there were no allergen-induced changes in BALF numbers of macrophages, lymphocytes, epithelial cells, or mast cells (as assessed by concentrations of cell-associated histamine). beta-Glucuronidase activity was significantly increased in BALF of guinea pigs at 2 h and 17 h following challenge. The degree to which eicosanoids can be recovered in BALF was investigated by instilling a range of tritiated compounds into the lungs of normal guinea pigs at the time of lavage. Ratio high-performance liquid chromatography revealed that there had been little metabolism of the eicosanoids recovered in BALF. However, there was evidence for a rapid removal of these mediators from the lung, a process which will militate against their accurate quantitation in BALF. Histamine, prostaglandin D2, and thromboxane B2 were detected in BALF but did not differ between treatment groups, and levels showed no simple relationship with the other inflammatory changes measured.

Albumins↗
PubMed1991

Mast cell numbers and staining characteristics in the normal and allergic human conjunctiva.

In this study we report the numbers and metachromatic dye-staining characteristics of mast cells (MCs) in the conjunctiva of normal subjects and patients with seasonal allergic conjunctivitis caused by pollenosis. In addition, we have used a monoclonal antibody to the MC-specific enzyme, tryptase, to enumerate tryptase-positive cells immunohistochemically. Tarsal conjunctival MCs were found to be present in increased numbers in the allergic compared to the nonallergic subjects. Most of the MCs exhibited staining that was formaldehyde resistant, compatible with their identification as connective tissue MCs or basophils. The high positive staining for tryptase confirmed that the metachromatic cells stained with toluidine blue were MCs and not basophils, both in normal and allergic subjects.

Adult↗
PubMed1991

Mast cell tryptase and histamine concentrations in bronchoalveolar lavage fluid from patients with interstitial lung disease.

1. Mast cell activation in the lung was investigated by measuring concentrations of mast cell tryptase and histamine in the bronchoalveolar lavage fluid from patients with bronchial carcinoma, sarcoidosis, extrinsic allergic alveolitis or cryptogenic fibrosing alveolitis and from normal subjects. 2. Histamine concentrations in bronchoalveolar lavage fluid supernatants were elevated in the bronchial carcinoma and cryptogenic fibrosing alveolitis groups, and were correlated with the histamine content of the cells recovered. 3. An avidin-biotin-enhanced antigen-capture e.l.i.s.a., using polyclonal rabbit antibody specific for tryptase, and mouse monoclonal antibody AA5, allowed the quantification of tryptase in all samples of bronchoalveolar lavage fluid. Tryptase concentrations were increased in the bronchial carcinoma and extrinsic allergic alveolitis groups and in some of the patients with sarcoidosis, and the levels correlated with mast cell numbers and also with concentrations of albumin. 4. There was no significant correlation between levels of tryptase and histamine, suggesting differences in the rates of metabolism or different cellular sources. 5. The tryptase and histamine concentrations measured suggest that there is continuous degranulation of mast cells within the normal lung, but that this process is more pronounced in patients with bronchial carcinoma or interstitial lung disease.

Adult↗
PubMed1991

Biological properties of human skin mast cells.

Mast cells and basophils, although sharing many constitutive properties, are quite distinct in their development, functions and biological properties. Mast cell granules are composed of a macromolecular matrix of proteoglycan and neutral protease of which heparin and tryptase, respectively, are predominant. The distribution of the other major neutral protease, chymase, allows human mast cell subpopulations to be subdivided immunocytochemically. All human mast cells respond to IgE-dependent stimulation with the secretion of the preformed mediator, histamine, and the newly generated lipid-derived eicosanoids PGD2 and LTC4. Although amounts of these products vary between mast cells dispersed from different tissues, it is uncertain whether this reflects true heterogeneity. Mast cells of the human skin, but not those of other tissues, are sensitive to stimulation by substance P, compound 48/80 and other basic non-immunological stimuli. The mechanism of mediator secretion induced by these agents is distinct from that induced by IgE-dependent stimulation. However, the morphological characteristics of degranulation are similar, suggesting that the distinct biochemical pathways merge into a common pathway before effecting degranulation.

Humans↗
PubMed1991

Mediator secretion from human skin mast cells provoked by immunological and non-immunological stimulation.

Mast cells of the human skin not only release mediators following immunological activation, but may also be stimulated to release histamine by the neuropeptides substance P, vasoactive intestinal polypeptide and somatostatin or by other basic secretagogues such as morphine, poly-L-lysine and compound 48/80. Release of histamine under these conditions is rapid and accompanied by minimal generation of the eicosanoids, prostaglandin (PG)D2 and leukotriene (LT)C4. Transient elevations of intracellular calcium are associated with mediator secretion induced by both stimuli, that induced by anti-IgE being derived from extracellular sources through channels in the plasma membrane while that stimulated by neuropeptides is mobilized intracellularly. Similarly, elevations of intracellular cyclic adenosine monophosphate (AMP) induced by anti-IgE occur only in the presence of extracellular calcium whereas with substance P elevations are apparent even in the absence of extracellular calcium. With the latter stimulus, histamine release is complete before the peak cyclic AMP is achieved. Histamine release stimulated by both secretagogues is unaffected by sodium cromoglycate or nedocromil sodium but is reduced by both salbutamol and isobutylmethylxanthine. Despite these biochemical and temporal differences, degranulation induced by both secretagogues proceeds by compound exocytosis which is indistinguishable under the electron microscope.

Calcium↗
PubMed1991

Neuropeptide-induced secretion from human skin mast cells.

Unlike human mast cells associated with mucosal surfaces such as lung, adenoids, tonsils and intestine, skin mast cells may be stimulated to release histamine by the neuropeptides substance P, vaso-active intestinal polypeptide and somatostatin or by other basic secretagogues such as morphine and compound 48/80. Release of histamine by neuropeptides is rapid and accompanied by minimal generation of the eicosanoids prostaglandin D2 and leukotriene C4. Transient elevations of intracellular calcium are associated with mediator secretion induced by both immunological and non-immunological stimulation, that induced by anti-IgE being derived from extracellular sources through channels in the plasma membrane while that stimulated by neuropeptides is mobilized intracellularly. Similarly, elevations of intracellular cyclic AMP induced by anti-IgE occur only in the presence of extracellular calcium, whereas with substance P elevations are apparent even in the absence of extracellular calcium. With the latter stimulus, histamine release is complete before the peak cyclic AMP is achieved. Despite these biochemical and temporal differences, degranulation induced by both secretagogues proceeds by compound exocytosis which is indistinguishable under the electron microscope. From these results we suggest that IgE-dependent and neuropeptide stimulation of human skin mast cells proceed by distinct biochemical pathways which eventually merge to produce exocytosis of their preformed granule-associated mediators.

Amino Acid Sequence↗