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Biomedical subjects

P C Atkins

Publications and source records attributed to P C Atkins.

At least 37 records · Page 2Linked to original sources
PubMed1990

In vivo antigen-induced cutaneous mediator release: simultaneous comparisons of histamine, tryptase, and prostaglandin D2 release and the effect of oral corticosteroid administration.

To determine if basophils were responsible for the persistent release of histamine during continuous antigen (Ag) administration in the skin, we compared the release of histamine, tryptase, and prostaglandin D2 (PGD2) at sites of continuous (5 hours) and intermittent Ag and codeine skin-chamber challenge in the skin of 16 atopic and four nonatopic subjects. In addition, we compared the release of these three mediators at sites of continuous Ag challenge in five subjects during oral administration of 1 mg/kg of methylprednisolone. Continuous Ag challenge induced an initial (first hour) peak of histamine release followed by a lower level plateau of histamine release during the next 4 hours. The level of histamine release during the second to fifth hours was significantly higher at these sites of continuous Ag challenge than at the codeine- or intermittent Ag-challenge sites. Levels of both tryptase and PGD2 were increased after the first hour of Ag or codeine challenge, and tryptase decreased progressively thereafter at all sites. In corticosteroid-treated subjects, the persistent histamine release during the second to fifth hours of Ag challenge was significantly reduced. In contrast, corticosteroid therapy did not affect histamine release during the first hour of Ag challenge nor the release of PGD2 or tryptase at any time period. These findings suggest that basophils are the source of the persistent histamine release at sites of continuous in vivo Ag challenge, since such release (1) was unaccompanied by release of tryptase or PGD2 (released from mast cells but not basophils), (2) did not occur after codeine challenge that activates mast cells but not basophils, and (3) was inhibited by steroids that inhibit the accumulation and release of histamine from basophils but not mast cells.

Administration, Oral↗
PubMed1990

Determinants of in vivo histamine release in cutaneous allergic reactions in humans.

To determine host factors influencing the magnitude of mediator release during ongoing cutaneous allergic reactions in humans, we compared, in 22 subjects, the first-hour, second- to fifth-hour, and total (0 to 5 hours) skin chamber histamine release to (1) the in vitro reactivity and sensitivity of basophils to antigen for histamine release and (2) skin test sensitivity and reactivity to antigen, histamine, and codeine. There was no significant correlation between the first-hour and second- to fifth-hour histamine release. With a combination of basophil, antigen, histamine, and codeine skin sensitivity and reactivity, 64% to 75% of the magnitude of the first-hour, second- to fifth-hour, and total (0 to 5 hours) skin chamber histamine release could be accounted for. We conclude that antigen-induced in vivo allergic responses are a complex phenomenon dependent, in part, on antigen sensitivity, basophil and mast cell reactivity, and end organ responsiveness to mediators.

Adolescent↗
PubMed1990

Release of histamine and tryptase during continuous and interrupted cutaneous challenge with allergen in humans.

To help in understanding the patterns of in vivo mediator release in human allergic skin reactions, we have used a skin chamber model to challenge the denuded bases of skin blisters of 11 sensitive subjects with pollen antigens (Ags) and codeine (C), a mast cell degranulator. Challenges were performed either (1) continuously for 6 hours or (2) in an intermittent fashion that is, Ag or C for the first hour, buffer for the next 4 hours, and then Ag or C during the sixth hour. Fluids in the overlying chamber were assayed for levels of the mast cell components, histamine and tryptase. There was peak release of both histamine and tryptase during the first hour of Ag incubation (89 +/- 11 ng/ml and 1428 +/- 260 ng/ml, respectively). At continuous Ag-challenge sites, there was a plateau of histamine levels (8.0 to 9.5 ng/ml) during the next 4 hours, whereas tryptase levels decreased progressively to baseline levels. Challenge of continuous Ag-incubation sites with C, a mast cell activator, led to another peak release of both histamine and tryptase. At interrupted Ag-challenge sites, histamine levels decreased abruptly, and tryptase levels decreased progressively after the first hour. Rechallenge of such sites with Ag during the sixth hour induced a peak release of histamine but no increase in tryptase levels. Continuous challenge with C for up to 5 hours in other sites induced an initial peak histamine release without a subsequent plateau. However, such a plateau of histamine (but not tryptase) release occurred after an initial C challenge if Ag was subsequently incubated in a continuous fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Platelet-activating factor- and leukotriene B4-induced release of lactoferrin from blood neutrophils of atopic and nonatopic individuals.

We found increased accumulation of neutrophils and their components, lactoferrin (Lf) and elastase, as well as platelet-activating factor (PAF) and leukotriene B4 (LTB4) at sites of ongoing human allergic reactions. To determine whether PAF or LTB4, could be the stimulus for in vivo Lf release, blood neutrophils of 17 subjects were incubated with PAF, LTB4, or the phorbol ester, phorbol myristate acetate (PMA), and the released Lf (ELISA assay) was compared with spontaneous release. Significantly increased Lf release was induced by PAF, 10(-5) to 10(-8) mol/L (p less than 0.002); LTB4, 10(-7) to 10(-8) mol/L (p less than 0.004); and PMA (0.05 micrograms/ml) in a dose-dependent reaction. Cytochalasin was not required for Lf secretion but did enhance such responses. PAF-induced Lf secretion was inhibited by the specific PAF antagonist, BN 52063. More Lf was released from neutrophils of atopic than from nonatopic subjects in response to PAF, 10(-6) mol/L (4.2 micrograms/ml +/- 0.2 versus 2.6 micrograms/ml +/- 0.2; p less than 0.001) but not to LTB4, PMA, or buffer (p, not significant). We conclude that (1) PAF and LTB4 released in vivo could stimulate local neutrophils to release Lf with possible pathogenic effects and (2) neutrophils of atopic subjects are more responsive to PAF than neutrophils of nonatopic subjects in this regard.

Adult↗
PubMed1989

Late appearance of phospholipid platelet-activating factor and leukotriene B4 in human skin after repeated antigen challenge.

Inflammatory mediators were assessed in supernatants of chamber fluids from eight ragweed- or grass-sensitive subjects during antigen-induced cutaneous inflammatory responses. Platelet activating factor (PAF) accumulated at concentrations of 1 pm to 90 mumol/L in six of eight subjects beginning at 3 hours and continuing for 9 hours after antigen challenge. Leukotriene B4 (LTB4) was detectable at cutaneous sites of antigen challenge in five of five subjects throughout the 9-hour period at levels from 1 to 36 nmol, a range of 38% to 80% of which were omega-oxidation metabolites. Histamine levels peaked in the first hour at 106 +/- 18 ng/ml and decreased to a plateau of 11 to 13 ng/ml at 3 to 9 hours after antigen challenge. No PAF and only very low levels of LTB4 (0.1 to 1.3 nmol) and of histamine (less than 2 ng/ml) were detected at buffer-control sites during the 9 hours of study. Continuous antigen exposure thus results in the persistent release of histamine and LTB4 and the late appearance of PAF, all of which may contribute to the chronicity of allergic disorders and may have a bearing on the IgE-mediated, late-phase cutaneous response.

Adult↗
PubMed1989

Identification of leukotriene B4 as the neutrophil chemotactic factor released by antigen challenge from passively sensitized guinea pig lungs.

Neutrophils are prominent in some IgE-mediated allergic reactions and may contribute to the pathophysiology of immediate hypersensitivity. Antigen challenge of fragments of guinea pig lung tissue that were passively sensitized with IgE or IgG antibody evoked the release of neutrophil chemotactic activity (NCA) in parallel with histamine. The NCA released from lung tissue by both IgG- and IgE-dependent stimulation coeluted from a column of Sephacryl S-300 with synthetic leukotriene B4 (LTB4). The NCA in eluates from the Sephacryl S-300 column contained LTB4, as determined by high-performance liquid chromatography and specific radioimmunoassay, in quantities that accounted for the observed chemoattractant activity in the eluates. Furthermore, the NCA of supernatants from antigen-challenged lung fragments was reduced by a mean of 80% after absorption with a monoclonal antibody to LTB4. LTB4 thus constitutes the major functional constituent of NCA released after anaphylactic challenge of IgE- and IgG-sensitized guinea pig lung tissue.

Anaphylaxis↗
PubMed1988

Release of histamine and tryptase in vivo after prolonged cutaneous challenge with allergen in humans.

The patterns of in vivo release of histamine and tryptase were determined during prolonged Ag incubation in atopic individuals, using skin chambers placed over denuded skin blister sites. However, the patterns of histamine and tryptase release over a period of up to 9 h of Ag exposure were different. Whereas rates of release of both histamine and tryptase peaked within 1 h in an Ag dose-response fashion, that of tryptase decreased progressively thereafter and was not different from buffer challenge sites from the 5th to 9th h at all concentrations of Ag tested. The rate of histamine release reached a plateau after 2 h and remained at a constant low level throughout the 3rd to 9th h of Ag incubation. Rechallenge of the sites continuously exposed to Ag with a different second Ag at the 6th h resulted in a second peak of release of both histamine and tryptase. This persistence of in vivo histamine but not tryptase release during the later time points of the cutaneous allergic response differs from what has been demonstrated in vitro with dispersed mast cells. Whether this reflects basophil participation at these time points or an as yet undetermined mechanism for release of histamine but not tryptase by mast cells is not known. These novel patterns of mediator release after prolonged Ag exposure in vivo may have clinical relevance to allergic diseases during which atopic subjects are exposed to Ag over several hours to days.

Adult↗
PubMed1988

Platelet activating factor increases expression of complement receptors on human neutrophils.

The phospholipid inflammatory mediator platelet activating factor (PAF) has been shown to stimulate certain functions of polymorphonuclear leukocytes (PMN). However, the effect of PAF on surface complement receptors of PMN has not been described. Using monoclonal antibodies and flow cytometry, we have assessed the effects of PAF on surface expression of membrane receptors for C3bi (CR3) and C3b (CR1) in human PMN. PAF (optimal concentration of 1 x 10(-8) M) increased CR3 190% and CR1 174% compared with unstimulated cells at 37 degrees C, while the PAF analogue lyso-PAF had no stimulatory effect. Both CR3 and CR1 responses to PAF reached maximum levels at 15-30 min. PAF effects were comparable to peak effects induced by LTB4 but less than induced by FMLP. A PAF receptor antagonist, SRI 63-441, blocked the increased complement receptor expression in a dose-dependent manner with maximal inhibition of 80-95% at 5 x 10(-6) M. Extracellular calcium had no effect on CR1 expression but slightly enhanced and EGTA partially inhibited the PAF-induced increase in CR3 expression. Simultaneous incubation with PAF and LTB4 enhanced CR3 and CR1 expression more than either agent alone. These findings indicate that PAF, alone and in combination with LTB4, can induce altered expression of complement receptors on the surface of PMN. This effect may enhance adhesion and phagocytosis by PMN at inflammatory reaction sites.

Calcium↗
PubMed1988

Late onset reactions in humans: correlation between skin and bronchial reactivity.

We carried out sequential measurements of the intensity of simultaneously occurring late onset skin and bronchial reactivity in seven atopic subjects following skin and inhalation challenge with pollen antigen. All subjects demonstrated dual bronchial and cutaneous reactions. Although the intensity of the late onset bronchial responses correlated temporally and quantitatively with the degree of increase in serum neutrophil chemotactic activity, the intensity of the late onset skin responses correlated with the level of specific antigen-IgE in the serum. This suggests that even in the same subjects, different factors govern the intensity of late onset skin and bronchial responses.

Bronchial Provocation Tests↗
PubMed1987

Activation of plasma Hageman factor and kallikrein in ongoing allergic reactions in the skin.

Ten atopic subjects, sensitive to intradermal injection of less than or equal to 10 protein nitrogen units of ragweed or grass pollen antigen, underwent paired antigen and buffer skin chamber incubation over the base of denuded skin blisters. The chamber fluids were sampled over a 6-hr period for histamine and activated Hageman factor and plasma kallikrein which were complexed to C1 inhibitor. In 9 of 10 subjects significantly (p less than 0.01) increased histamine levels (74 +/- 11 ng/ml vs 1.5 +/- 0.55 ng/ml) and kallikrein-C1 inhibitor complexes (2.15 +/- 0.78 ng/ml/hr vs 0.51 +/- 0.09 ng/ml/hr, p less than 0.25) were detected at antigen sites compared with buffer sites, respectively. Increased levels of activated Hageman factor (ng/ml/hr) were detected at antigen sites (1.35 +/- 0.60) compared with buffer sites (0.11 +/- 0.05), (p less than 0.01), in 8 of 10 subjects. Whereas peak levels of histamine were obtained after 1 hr of challenge, both Hageman factor and kallikrein activation, as assessed by complex formation, tended to peak later from the 2nd to the 5th hr. This represents the first demonstration that cutaneous IgE-mediated allergic responses are associated with local activation of the intrinsic plasma coagulation-kinin pathways.

Adult↗
PubMed1987

Increased expression of CR3 (C3bi receptor) on neutrophils in human inflammatory skin reactions.

To help determine whether the neutrophils (PMN) found in skin inflammatory reactions are activated, we have compared the expression of the C3bi receptor (CR3) on such cells with that on autologous blood PMN in 10 pollen-sensitive subjects. Using skin chambers overlying denuded blister bases we collected PMN at 2 or 4 hr at sites of challenge with pollen antigen or buffer solution. These cells and PMN in autologous blood were incubated with monoclonal anti-CR3 antibody and the expression of CR3 was measured by indirect fluorescence and flow cytometry. Significantly more PMN were found at antigen than at buffer sites at 2 hr (7.02 +/- 0.45 X 10(5) vs 0.71 +/- 0.25 X 10(5] and at 4 hr (2.2 +/- 0.57 X 10(6) vs 5.47 X 10(5). The mean CR3 expressions on PMN at antigen and buffer sites were similar (117 +/- 7.4 vs 118 +/- 9.0); both were significantly greater than on blood PMN (17.6 +/- 1.5; P less than 0.005). PMN from both sites could be stimulated further in vitro with formyl-methionyl-leucyl-phenylalanine (FMLP) to express more CR3 to a level even greater than in FMLP-stimulated blood PMN (155 +/- 11 and 157 +/- 12, respectively, vs 108 +/- 7 in blood PMN). The incubation of blood PMN with the noncellular component of the chamber fluid led to a moderate (28-100%) increase in CR3 expression, but far less than the CR3 expression on the chamber fluid PMN themselves. Since surface CR3 is thought to be an activation marker important in PMN adhesion, these findings may be important in understanding the emigration of PMN in skin inflammatory reactions.

Adult↗
PubMed1987

Cellular inflammatory responses in human allergic skin reactions.

To define better the role of inflammation in the response to pollen antigens, we have used our skin chamber model to study inflammatory cells recovered from the sites of ongoing allergic reactions. In 15 atopic subjects, paired skin blister sites were simultaneously challenged with ragweed- or grass-pollen antigen or buffer for 5 hours. There were 10 times as many cells recovered at antigen (20.7 X 10(5)) than at buffer (2.0 X 10(5)) sites, p less than 0.005; greater than 97% of the cells recovered were neutrophils. The number of cells recovered at the antigen sites correlated with the total amount of histamine released (r = 0.57; p less than 0.05) but not with the extinction dilution skin test reactivity nor with the intensity of the late cutaneous allergic response measured 6 hours after the injection of antigen. Phase-contrast microscopic examination of the cells recovered from the antigen sites demonstrated that 82% to 95% were polarized compared to 0% to 1.5% of autologous blood neutrophils obtained simultaneously from the peripheral blood. Antigen site cells were as capable of serum-dependent phagocytosis as peripheral blood neutrophils. There was no significant difference in the migratory response to buffer, the chemoattractant N-formyl-methionyl-leucyl-phenylalanine, or leukotriene B4, but there was a significantly decreased response to platelet-activating factor when the cells recovered from antigen sites were compared to autologous blood neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens↗
PubMed1987

Neutrophil activation in human inflammatory skin reactions.

To determine the functional activity of neutrophils emigrating to the sites of ongoing human allergic inflammatory reactions, we assessed the intensity of their intracellular oxidative metabolism by measuring the intracellular oxidation by H2O2 of the dye, 2',7'-dichlorofluorescein diacetate (DCFH-DA), to fluorescent 2',7'-dichlorofluorescein. The intensity of intracellular fluorescence was measured by flow cytometry. In 13 atopic subjects, two denuded skin blister bases were challenged for 5 hours with pollen antigen and two blister bases with buffer. Both the level of histamine and mean number of cells recovered at antigen sites were greater than at buffer sites. Oxidation of DCFH-DA by neutrophils recovered from both antigen and buffer sites was significantly greater than that of autologous peripheral blood neutrophils (PBNs), reflecting an increase in the spontaneous generation H2O2 of cells recovered from the sites of inflammation. DCFH-DA oxidation by cells recovered from sites of antigen incubation was significantly greater than cells from buffer site incubations. Neutrophils from both antigen and buffer sites could be stimulated further in vitro by phorbol myristate acetate to the same level of H2O2 generation as phorbol myristate acetate-stimulated PBNs. In five subjects studied, the noncellular component of chamber fluids collected at 1 and 5 hours stimulated PBNs to increase their oxidative metabolism by 42% to 62%; however, this increased level of intracellular H2O2 was still much less than the spontaneous H2O2 generation observed in cells recovered from sites of allergic inflammation. The increased oxidative metabolism of neutrophils in human allergic and inflammatory skin reactions has important pathophysiologic implications for the role of these cells in inflammatory responses.

Adult↗
PubMed1987

Release of tryptase together with histamine during the immediate cutaneous response to allergen.

Better in vivo techniques are needed for objective assessment of mast cell-dependent events. Tryptase, a neutral protease selectively concentrated in human mast cells, appears along with histamine in skin chamber fluid overlying sites of allergen challenge in sensitive human subjects. Maximal amounts of histamine were found 0 minutes to 30 minutes after challenge; maximal amounts of tryptase were found 30 minutes to 60 minutes after challenge. The later appearance of tryptase most likely reflects its slower diffusion through tissue after release of tryptase from cutaneous mast cells as a macromolecular complex with proteoglycan. The mean weight ratio of tryptase (134,000 molecular weight tetramer) to histamine (111 molecular weight) in chamber fluid after allergen challenge during a 1-hour time course was 4:1. Total amounts of tryptase and histamine recovered in the 0.3 ml chamber fluid samples after a 1-hour challenge averaged 95 ng and 26 ng, respectively. Tryptase levels in skin chamber fluid are an accurate indicator of mast cell activation.

Adolescent↗
PubMed1987

In vivo effects of corticosteroids on human allergic responses. I. Effects of systemic administrations of steroids.

In order to better understand the effects of corticosteroids in allergic disease, the relative degrees of allergen-induced cutaneous histamine release and granulocyte accumulation were evaluated in atopic volunteers following intravenous placebo or methylprednisolone administration. In nine subjects, a single intravenous dose of methylprednisolone (1 mg/kg) did not inhibit histamine release but did significantly reduce granulocyte accumulation at both allergen and buffer-challenged sites during five and one-half to six and one-half hours following steroid injection. These findings suggest that the corticosteroid-induced anti-inflammatory effects at allergic reaction sites do not include inhibition of local mediator release. Furthermore, the steroid-induced inhibition of inflammatory cell accumulation is not specific for the allergic reaction.

Administration, Oral↗