Eliot H. Dunsky

Effects of theophylline, terbutaline, and prednisone on antigen-induced bronchospasm and mediator release

Eleven subjects demonstrating clinical, skin, and inhalation sensitivity to grass or ragweed pollen underwnet serial inhalation challenges, with and without orally administered theophylline, terbutaline, and prednisone. Comparisons of antigen sensitivity and mediator release were made during these challenges. All three drugs significantly reduced antigen sensitivity (PD20 inhalation units increasing from 670 to greater than or equal to 3,280). Peak plasma histamine levels after antigen challenge decreased from 11.4 ng/ml to less than or equal to 3.4 ng/ml during all drug administrations. Similarly, the percent increase in serum neutrophil chemotactic activity (NCA) also decreased, from 96% to less than or equal to 36% during drug administrations. However, even at antigen doses resulting in bronchospasm during drug administration the systemic appearance of NCA and histamine were reduced. We conclude that prednisone, theophylline, and terbutaline significantly reduce antigen-induced bronchospasm and mediator release. The occurrence of bronchospasm despite the inhibition of histamine and NCA suggests either that the local concentration of these mediators are critical or that other mediators produce the bronchospasm observed.

Early effects of corticosteroids on basophils, leukocyte histamine, and tissue histamine

The comparative effect in 11 atopic subjects of a single intravenous injection of methylprednisolone on sequential studies of blood eosinophils, basophils, leukocyte sensitivity to antigen for histamine release, leukocyte histamine content, and skin histamine was examined. No significant changes occurred in any parameter after placebo treatment. In contrast, 4 hr after intravenous treatment with steroid there were significant decreases in mean eosinophil counts (-95%), basophil counts (-72%), and histamine content of 1 X 10(7) leukocyte samples (-62%). Temporal changes in the latter paralleled alterations in circulating basophil levels. No significant changes occured in the antigen histamine release sensitivity, or the total skin histamine. Studies over a longer period after steroids in 4 subjects showed eosinophil and basophil levels at a nadir at 8 hr, remaining suppressed for 24 hr, and returned to pretreatment levels by 72 hr. Results suggest that corticosteroids induce a prominent decrease in leukocyte histamine due to a depletion of basophils without a decrease in histamine content per basophil, and that skin tissue histamine stores remain unchanged by such treatment.

Patterns of mast cell alterations and in vivo mediator release in human allergic skin reactions

Patterns of in vivo histamine release in skin sites challenged with ragweed antigen were compared in five human subjects sensitive to this antigen and four nonallergic individuals, using a newly developed skin-chamber technique. These findings were compared with inflammatory cell responses in the reaction sites and patterns of ultramicroscopic mast cell alterations in biopsy specimens of skin tests in the same subjects. Definite mast cell alterations occurred within 15 sec and appeared maximal within 5 to 10 min after antigen injection. Histamine levels in appended chambers increased after a lag of 10 to 30 min and were elevated for at least 60 min after antigen challenge. Eosinophils accumulated only in antigen-induced reaction sites. However, there was no precise quantitative correlation among the degree of change in these three measurements. These appear to be promising approaches to further in vivo studies of human allergic reactions.

Histamine release and complement changes following injection of contrast media in humans.

Mechanisms responsible for allergic-like reactions following administration of radiographic contrast media (RCM) are unclear. Aortic root blood specimens were obtained sequentially in 6 subjects following injection of RCM into the pulmonary artery during cardiac catheterization. In 5 subjects, elevated plasma histamine levels (up to 80 ng/ml) occurred within minutes. Levels of C3, C4, factor B, and total hemolytic complement activity were decreased in the same specimens. No hemodynamic or clinical abnormalities were noted. These findings support the concept that RCM can liberate histamine in vivo in humans. Complement alterations may be related to localized RCM-protein interaction. It is unclear whether complement changes are related to the RCM-induced allergic mediator release.

Comparison of plasma histamine and cyclic nucleotides after antigen and methacholine inhalation in man

Serial determinations of plasma histamine and cyclic nucleotides (adenosine monophosphate [AMP] and guanosine monophosphate [GMP]) were performed after inhalation of antigen and methacholine in four groups of subjects. In the first group, consisting of six antigen-sensitive subjects exhibiting bronchospasm after inhalation of ragweed or grass antigen, plasma histamine was elevated within 2 min and persisted for 30 min after inhalation of antigen. Peak histamine levels were between 18 to 80 ng/ml. In the second group, consisting of four nonatopic subjects, neither bronchospasm nor histamine was observed, despite inhalation of the same or 10-fold increased concentrations of antigen. In the third group, consisting of six subjects (three atopic and three nonatopic) exhibiting bronchospasm after inhalation of 2.5 to 10 mg of methacholine, sustained increases of histamine began at 1 min and persisted for 60 min after inhalation of methacholine. In the fourth group, seven subjects (two atopic, five nonatopic) without demonstrable bronchospasm despite inhalation of 2.5- to 10-fold increased doses of methacholine, no histamine was detected in the plasma at any time after inhalation of methacholine. Serial measurements of cyclic nucleotides showed no consistent changes in serum levels of cyclic AMP or cyclic GMP following inhalation challenge. We conclude that serum levels of histamine but not cyclic nucleotides change during bronchospasm induced by either antigen or methacholine.

The direct demonstration of histamine release in allergic reactions in the skin using a skin chamber technique

We have adapted a skin chamber technique to permit sampling of fluid at the skin window sites of pollen antigen-induced allergic reactions. Low background levels of histamines are formed in control chambers, whereas significantly increased (p less than 0.01) amounts are found within 30 min following ragweed application in sensitized subjects.

Histamine suppression of in vivo eosinophil accumulation and histamine release in human allergic reactions

Although it has been shown that histamine inhibits antigen-induced in vitro histamine release from basophils, it is unclear whether histamine inhibits in vivo mediator release in human allergic reactions. We report effects of exogenous histamine on histamine release and inflammatory cell responses in antigen-challenged skin sites in eight ragweed-sensitive individuals. Four heat-suction blisters in each subject were unroofed, and a collection chamber was appended to each blister base. Chamber A contained 1000 PNU/ml ragweed extract; chamber B contained buffered saline (control fluid); chamber C contained 1000 PNU/ml ragweed and 50 ng (5 x 10(-7) M) of histamine; and chamber D contained histamine alone (50 ng). Comparative analyses of chamber histamine levels in individual subjects showed that (1) histamine levels in chamber A were significantly greater than those in chamber B (p less than 0.01) and that histamine levels in chamber C were not significantly different than those in chamber D (p less than 0.5). Likewise, comparison of eosinophils attaching to membrane filters appended to the chamber bases for 2 hr showed that there were significantly more eosinophils in chamber A than in chamber B (p less than 0.01) and that there was no significant difference in eosinophil numbers on filters appended to chamber C vs chamber D. In three of four subjects studied, addition of exogenous histamine (50 ng/ml) to ragweed before intradermal injection inhibited the ultrastructural mast cell alterations seen within 10 min after injection of ragweed alone. In the one subject in which mast cell alterations were not prevented, exogenous histamine also did not inhibit antigen-induced histamine release or subsequent eosinophil accumulation in the skin chambers.

Histologic responses in human skin test reactions to ragweed: IV. Effects of a single intravenous injection of steroids

A controlled study has been carried out dealing with the early effects of a single intravenous dose of either methylprednisolone or placebo or newly developed and ongoing cellular inflammatory responses in immediate hypersensitivity skin test reactions. There was no significant difference in the tissue eosinophil responses to ragweed injected 2 hr before and 2 hr after placebo; there was a significant rise (101% +/- 39) from the second to fourth hour after antigen injection. By contrast, there was a marked decrease in the tissue eosinophil response to antigen injected 2 hr after steroids as compared to the pattern seen in the presteroid reaction. In addition, the eosinophil numbers not only did not increase from the second to fourth hour when steroids were injected at the second hour but decreased markedly. These findings suggest early suppressive effects on tissue eosinophil responses within 2 hr after steroid were administered intravenously. Also, there may be trafficking of eosinophils both into and out of these inflammatory sites during the first hours after intradermal antigen injection.

Effect of cimetidine on exogenous histamine inhibition of histamine release in vivo.

We previously reported that exogenous histamine inhibits in vivo histamine release and eosinophil accmulation in ragweed‐challenged skin sites of sensitive human subjectes. The mechanism(s) involved were unclear. In this study, we repeated similar approaches in of the same subjects pretreated for 3 days with cimetidine, an H2 receptor antagonist. The pattern of exogenous histamine effects was now different in that local exogenous histamine (50 ug/ml) did not significantly alter ragweed‐induced mast cell alteration, histamine release, or the degree of eosinophil accumulation in skin challenge sites. These findings suggest that the observed exogenous histamine inhibitory effects may be mediated through the H2 receptor.