On the basis of the experiments described here, we suggest that the mechanism of action of SRS in guinea pig ileal longitudinal muscle is very similar to that used by other agonists in this preparation, namely interactions at a specific receptor to activate Ca++ channels leading to Ca++ influx and mechanical response. SRS responses differ in 1 important respect from those produced by other agonists. SRS and leukotriene D cause the generation of a slower contraction, which has a greater resistance to reversal by washing. The basis for this unique and prolonged duration of action is unknown but may represent an exceptionally tight, or even irreversible, association with a membrane component. Current studies on the structure of SRS may be helpful in this regard. Although not definitive, this report clearly indicates that a SRS "receptor" is, in fact, present on smooth muscle and that it utilizes a pool of calcium channels common to all smooth muscle agonists.
Fragments of human lung parenchyma were passively sensitized with ragweed IgE in vitro, and subjected to antigenic challenge in experiments designed to explore the genesis of arachidonate metabolites during lung anaphylaxis. Lung supernatant was sampled serially and examined for histamine as a marker of mast cell activation, and prostaglandins E F'a, and 13,14-dihydro, 15-keto-PGF,a. In eight of nine human lung experiments, the kinetics of PGE, and PGF,a production were indistinguishable from that of histamine release. In all experiments PGF'a production (40.7 ± 7.1 ng PGF'a/g of lung tissue) was large compared with PGE production (4.0 ± 1.0 ng PGE/g of lung tissue). When lung fragments were challenged with high concentrations of 3 smooth muscle contractants (histamine, methacholine, and KCI), PGF'a production was only 5 to 200/0 of that seen with optimal antigenic challenge of the same tissue. On this basis we concluded that neither released histamine, either directly or indirectly, nor smooth muscle contraction per se was primarily responsible for the large PGF'a production during lung anaphylaxis. Passively sensitized human bronchial tissue was evaluated in an organ bath for PGF'a and PGE production and tension development after sequential challenge with histamine (10-' M), methacholine (10-' M), and optimal dose antigen. In contrast to lung parenchyma, for sensitized bronchial tissue, (a) PGE production predominated as much as fivefold over PGF'a production after challenge with each of the 3 stimuli, and (b) the quantity of PGF,a produced was similar in some but not all lung specimens for antigen challenge as for challenge with histamine or methacholine. We concluded that in bronchi, unlike that in parenchyma, PGE and PGF'a production may be largely accounted for in some but not all lung specimens by the effect of spasmogenic mast cell mediators, such as histamine, on smooth muscle or associated tissues. Based on these observations and published data, it seems unlikely that the mast cell itself is a major source of the bronchospastic PGF'a production during anaphylaxis in lung parenchyma. The most likely origin of the PGF'a is an undetermined cell type (or types) that is relatively abund!mt in lung parenchyma compared with that in bronchial tissue. The secondary stimulus for PGF'a production during lung anaphylaxis remains unknown.
Fragments of human lung parenchyma were passively sensitized with ragweed IgE in vitro, and subjected to antigenic challenge in experiments designed to explore the genesis of arachidonate metabolites during lung anaphylaxis. Lung supernatant was sampled serially and examined for histamine as a marker of mast cell activation, and prostaglandins E2, F2α, and 13,14-dihydro, 15-keto-PGF2α. In eight of nine human lung experiments, the kinetics of PGE2 and PGF2α production were indistinguishable from that of histamine release. In all experiments PGF2α production (40.7 ± 7.1 ng PGF2α/g of lung tissue) was large compared with PGE production (4.0 ± 1.0 ng PGE/g of lung tissue). When lung fragments were challenged with high concentrations of 3 smooth muscle contractants (histamine, methacholine, and KCl), PGF2α production was only 5 to 20% of that seen with optimal antigenic challenge of the same tissue. On this basis we concluded that neither released histamine, either directly or indirectly, nor smooth muscle con...
This study was based on the premise that mediator release plays a role in the pathogenesis of allergen-induced as well as nonallergen-induced asthma. We studied histamine release from human basophils obtained from patients with asthma and from control subjects. These cells were challenged with several different stimuli: goat anti-human IgE-Fc, C5-peptide, N-formyl-methionyl-leucyl-phenylalanine (f-met peptide), Ca++ ionophore A23187, hyperosmolar mannitol, and D2O. Release induced by any one stimulus was unrelated to the response to any other stimulus. The basophils of patients with asthma and control subjects responded similarly to most stimuli: they were significantly less responsive to C5-peptide and f-met peptide, and significantly more responsive to D2O. The results suggest that there is a parameter of releasibility that must be defined for each separate stimulus, and that patients with asthma can be differentiated from normal persons by the response of their basophils to selected stimuli.
Adenosine, at physiologic concentrations, inhibits in vitro IgE-mediated human basophil histamine release in a dose-dependent fashion. The inhibition dose-response curve is paralleled by an adenosine-induced increase in cAMP levels of human leukocyte preparations. Further evidence that the adenosine effect is related to changes in cAMP levels is that the nucleoside inhibits only in the first stage of antigen-induced histamine release and fails to inhibit the release caused by ionophore A23187. A poorly metabolized derivative of adenosine, 2-chloroadenosine inhibits as effectively as adenosine; dipyridamole, which blocks adenosine uptake, does not impair the inhibition caused by adenosine. Finally, theophylline, which is a competitive antagonist of adenosine in human lymphocytes also blocks the inhibition of release caused by adenosine. These data suggest that adenosine acts via a specific cell-surface receptor linked to adenylate cyclase. It appears that the human basophil has a specific receptor for adenosine and that this nucleoside may modulate the in vivo release of the mediators of immediate hypersensitivity reactions.
