Anaphylatoxin-induced shock and two patterns of anaphylactic shock: hemodynamics and mediators.

In the dog, different cardiorespiratory reactions were identified in two types of anaphylactic shock and in C5a-AT (anaphylatoxin)-induced shock. All three types had in common a portal blood pooling with consequent decrease in the venous return, cardiac output, and arterial pressure. In anaphylaxis (a) of the first type, at a low titer of hemagglutinating antibodies, the latent period was 68 s and heart and lung function was unchanged. In the second type, at high titer, the latency was 19 s and pulmonary hypertension and decreased heart contractility occurred. After AT injection pulmonary hypertension appeared with tachypnea and unchanged heart function. Tachyphylaxis, but not cross-over tachyphylaxis against the anaphylactic agent and AT was observed in dogs and isolated guinea pig lungs. AT induced a transient release and a, a prolonged release of histamine, prostaglandins (PGs), and thromboxane A2 and endoperoxides from guinea pig lungs. SRS-A was released only in a. Indomethacin inhibited AT-induced release of PGs in guinea-pig lungs and AT-induced hypotension in the dog though it did not prevent the drop in cardiac output. These model studies suggest that different patterns of clinical a. can occur, depending on the type of antibodies and/or mediators involved.     

The dynamics of the change in complement titer in guinea pigs during anaphylactic shock and under conditions of inhibition of the shock with dimedrol

Summary In guinea pigs with anaphylactic shock, provoked by injection of specific antigen, the complement titer usually dropped in one hour after its administration, the reduction being maximal in 3–4 hours. In the majority of animals, the complement level was restored in 24 hours after the shock. Preliminary administration of dimedrol prevented the anaphylactic shock and maintained the complement at the initial level in the guinea pigs.(Presented by Active Member AMN SSSR, N. N. Zhukov-Verezhnikov) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 51, No. 1, pp. 68–70, January, 1961     

Role of immunoglobulins G1 and G2 in anaphylactic shock in the guinea pig

Heating serum from actively sensitised guinea pigs did not remove its ability to sensitise recipient animals in vivo and parenchymal lung strips in vitro to anaphylaxis. Thermoresistant antibodies should thus account for the transferable sensitising effect, which persists for at least 9 days. IgG1 and IgG2, contained in the serum, were separated by affinity chromatography to determine the importance and the participation of these subclasses in passive anaphylactic shock. IgG1, present in smaller amounts than IgG2, was more effective in sensitising isolated lung strips. The intravenous administration of ovalbumin to guinea pigs, which had been injected with 0.8 mg/kg of IgG1 or 2 mg/kg of IgG2 9 days beforehand, induced an intense bronchoconstriction with leucopenia and moderate thrombopenia, suggesting an as yet undescribed role for IgG2 in passive tissue sensitisation. The use of mepyramine, an antagonist of the histamine H1 receptor, WEB 2086, an antagonist of platelet-activating factor, and nordihydroguaiaretic acid, a dual inhibitor of cyclooxygenase and lipooxygenase, alone or associated, demonstrated that the anaphylactic contraction of lung strips from guinea pigs sensitised by IgG1 is mediated by histamine and arachidonate derivatives, whereas that of lung strips from guinea pigs sensitised with IgG2 is mostly mediated by histamine. In addition, the association of the three potential antagonists slightly reduced the anaphylactic contraction of lung strips provided by guinea pigs sensitised by serum. Our results, using a sensitisation procedure considered until now to involve exclusively IgE antibodies, indicate that IgG1 and IgG2 are in fact the essential antibodies for passive anaphylactic shock in the guinea pig.     

Intratracheally applied rSP-C surfactant exhibits no anaphylactic shock reactions in a guinea pig model of acute lung hypersensitivity.

The effect of the intratracheal administration of the recombinant SP-C surfactant apoprotein (rSP-C) with phospholipids (PL) in comparison to an ovalbumin induced anaphylactic shock reaction was studied in guinea pigs lungs. Narcotized guinea pigs were challenged by intratracheal administration on test day 24/25 once with a suspension of rSP-C/PL (reconstituted suspension). These animals were priorily sensitized on test day 1, 3 and 5 intraperitoneally with rSP-C/PL suspension or with Ovalbumin (OV) respectively. The following groups were used to assess the anaphylactic lung shock symptoms: group 1: positive control, 1 mg/kg OV protein, 2 ml/kg application volume, (Appl. vol.), N: 5 animals; group 2: 1 mg rSP-C/50 mg PL/0.5 ml/kg Appl. vol., N: 10; group 3: 2 mg rSP-C/100 mg PL/1.0 ml/kg Appl. vol., N: 10; group 4: 4 mg rSP-C/200 mg PL/2.0 ml/kg Appl. vol., N: 10. Clinical signs, mortality, lung weights and histopathological changes were evaluated. Additionally the lungs were investigated immunohistologically with polyclonal antibodies against rSP-C to determine the pulmonary distribution of the intratracheal applied rSP-C. In the OV-treated positive control group, all animals died within 4 minutes after intratracheal challenge, while only 1 animal of group 4 died probably due to an narcosis related respiratory arrest. In the rSP-C/PL treated groups, the lung weights showed a dose-related increase, but nevertheless all these rSP-C-treated groups showed a significant lower lung weight in comparison to the OV treated positive control group. The histopathology assessment of the lungs in the OV-treated animals revealed a severe generalised bronchoconstriction and a hyperemia in connection with a slight interstitial edema in all five animals. The rSP-C/PL-treated animals, which were sacrificed after 3 days, showed no bronchoconstriction but a slight increase in the severity of bronchus-associated infiltration with eosinophilic granulocytes and in the formation of peripheral emphysema, but with no dose-dependency. A slight dose-dependent increase in the deposition of peribronchiolar eosinophilic foreign material was evident. In contrast to this, the number of lipid-laden alveolar macrophages seemed to decrease with increasing doses of rSP-C/PL. The immunohistological investigation with a polyclonal antibody against rSP-C showed an intraalveolar distribution of the intratracheally applied rSP-C which is mainly located in the peribronchiolar alveolar parenchyma. A rSP-C-positive staining was visible within the cytoplasm of alveolar histiocytes, type II pneumocytes and also as an extracellularly rim along the alveolar walls. The polyclonal antibody showed no cross reaction with natural occuring SP-C-protein of the guinea pigs. We conclude that the intratracheal application of the rSP-C surfactant containing phospholipids (PL) exhibits no significant risk of an anaphylactic shock reaction in this guinea pig lung hypersensitivity model. The immunohistological investigation with polyclonal antibodies against rSP-C demonstrated clearly the distribution of intratracheal applied material in this toxicological animal model.     

Suppression of the anaphylactic reaction of isolated smooth-muscle organs by potassium arsenite

The possibility of suppressing the anaphylactic reaction of human and guinea pig smooth muscle by means of inorganic arsenic was studied. Potassium arsenite (in the form of Fowler's solution) inhibited the development of anaphylactic contraction of human smooth muscle (ileum). Potassium arsenite completely blocked the development of anaphylactic bronchospasm and the liberation of biologically active substances from the lungs of guinea pigs.Allergologic Research Laboratory, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 9, pp. 341–343, September, 1977.     

Use of steroidal antiinflammatory drug provides further evidence for a potential role of PAF-acether in bronchial anaphylaxis

We presently demonstrate that PAF-acether (1-O-alkyl-2-O-acetyl-sn-glycerol-3-phosphoryl-choline) is formed by sensitized guinea pig lungs upon in vitro antigenic challenge. Pretreatment of the animals with a steroidal antiinflammatory drug, budesonide, almost totally suppresses this biosynthesis. Since budesonide inhibits the anaphylactic bronchoconstriction in actively sensitized guinea pigs, these data strongly support the assumption that PAF-acether is a mediator of bronchial anaphylaxis.     

Effect of Anaphylactic Shock on Suppressors of Cytokine Signaling

The pathophysiologic mechanisms of anaphylactic shock still remain unclear. In this study, we investigated the changes of expression and translation of SOCS1/SOCS3 in the heart, lungs, kidney, liver and spleen from patients who died of anaphylactic shock. Samples from the same viscera of 8 patients who died of anaphylactic shock and 8 healthy controls who died from accidents were collected in the present study. The level of IgE was measured in heart, and SOCS1/ SOCS3 mRNA and protein expression were determined by RT-PCR and immunohistochemistry, respectively. As a result, the higher IgE level was detected in the blood samples from the patients' heart than the control. SOCS1 and SOCS3 protein were significantly increased in the kidney and liver than the control. After anaphylactic shock, the expression of SOCS1 and SOCS3 mRNA were also increased. The expression level of SOCS3 mRNA was higher than that of SOCS1 in all viscera, and both were the highest in liver and kidney. There was a positive correlation between SOCS1 mRNA and SOCS3 mRNA in liver and kidney after anaphylactic shock. Our results indicate that SOCS1 and SOCS3 may play a regulatory role in anaphylactic shock viscera injury processes during anaphylactic shock.     

Quercetin inhibits anaphylactic contraction of guinea pig ileum smooth muscle

Certain flavonoids inhibit antigen-induced release of histamine from mast cells and basophils and also inhibit contraction of guinea pig ileum induced by histamine, acetylcholine, and PGE2. We examined the effect of one flavonoid, quercetin, on anaphylactic smooth muscle contraction of ileum from guinea pigs sensitized to egg albumin. Quercetin inhibited both the phasic and tonic components of anaphylactic contraction in a concentration-dependent fashion (IC50 approximately 10 microM). Whether this is primarily an effect on mast cell mediator release or inhibition of mediator effects on smooth muscle has not been established.     

Effect of SN-408 (salmeterol hydroxynaphthoate) on passive cutaneous anaphylaxis and anaphylactic chemical mediator release in rats and guinea pigs.

The influence of SN-408 (salmeterol hydroxynaphthoate), a new selective beta 2-stimulant, on homologous passive cutaneous anaphylaxis (PCA), histamine- or serotonin-induced skin reaction and anaphylactic chemical mediator release was investigated in rats and guinea pigs, and its efficacy was compared with that of salbutamol, isoproterenol or disodium cromoglycate (DSCG). Intravenous administration of SN-408 (0.1-10 micrograms/kg) 1 min before, the antigen challenge dose-dependently inhibited rat homologous PCA to a similar extent to salbutamol. The inhibitory effect of these beta-agonists was quickly attenuated along with time between the administration of the drug and the antigen challenge. SN-408, however, still showed significant inhibition at the time of administration 5 min before the antigen challenge at which other agonists did not significantly affect any more. Ten micrograms/kg of SN-408 exhibited approximately 50% inhibition of skin reaction induced by either histamine or serotonin in rats. In addition, the compound represented concentration-dependent inhibition of the anaphylactic histamine release from the isolated rat peritoneal exudate cell, indicating that the inhibitory effect of SN-408 on rat homologous PCA is due to the suppression of mediator release in addition to the antagonism to mediator(s) released. The anaphylactic release of either histamine, immunoreactive (i-) leukotriene (LT)B4 or i-LTC4 from guinea pig lung fragments was concentration-dependently inhibited by 10(-10)-10(-7) g/ml SN-408, and the inhibitory potency appeared to be enhanced by prolongation of the pretreatment interval with the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complement-Dependent Anaphylactic Reactions

The concept of elicitation of reactions of anaphylactic type by non-tissue-fixing antibody, through activation of complement and release of anaphylatoxins by antigen-antibody complexes in vivo, is not clearly defined by published evidence. Experimental data are presented to demonstrate that guinea pig immunoglobulin G2 (noncytotropic) complexed with antigen in vitro elicits dermal reactions in guinea pigs, and that pretreatment of animals with complement-inactivating cobra venom factor diminishes such reactions. The various pathways through which immediate hypersensitive reactions may occur are discussed.     

Anaphylactic shock in monkeys passively sensitized with human reaginic serum

Mechanisms inducing a low cardiac output (CO) state in IgE-mediated (cytotropic) anaphylactic shock in anesthetized Macaca irus monkeys were studied. 7 monkeys were sensitized by 2 i. v. injections of a human reaginic serum containing a high concentration of IgE antibodies against dog albumin. Anaphylactic shock was elicited 48 h after the last sensitization dose, by an i. v. injection of dog albumin. The severe anaphylactic shock which developed was characterized by an initial phase consisting of increased CO (+16%, mean value, 1 min after challenge), pulmonary hypertension and systemic vasodilatation followed by a phase consisting of decreased CO (-67%), a fall in mean arterial pressure from 113 to 45 mmHg, decreases in left and right arterial pressures (-5.3 and -3.2 mmHg, respectively) and increases in pulmonary vascular (+364%) and total peripheral (+30%) resistances. These changes were recorded 5 min after challenge and the values then remained essentially unaltered during the rest of the 30-min observation period. Pulmonary vascular resistance was only increased by 140% at the end of that period. Myocardial blood flow was maintained during shock at the expense of flow to other organs. However, initially there was a redistribution of blood flow withing the left ventricular myocardium, resulting in a relative decrease in subendocardial flow. This finding was not related either to occasional S-T changes in the electrocardiograms or to the level of decreased CO. The oxygen supply to the myocardium was reduced in shock but the reduction was always smaller than the corresponding decrease in heart work. Two additional monkeys sensitized with an IgE fraction from the human serum showed a smaller amount of specific IgE in their serum prior to challenge than the other monkeys. The response to challenge was milder, but resembled the initial vasodilatory reaction in monkeys sensitized with serum. These data on cytotropic anaphylaxis in the monkey show that the main cause of decreased CO and thus of the shock state is a decreased venous return, primarily due to peripheral blood pooling and, to a smaller extent, extravasation of plasma. No appreciable involvement of the heart in the induction of shock was detected.     

Intranuclear microtubules in lung mast cells of guinea pigs in anaphylactic shock.

Intranuclear microtubules were found in lung mast cells during anaphylactic shock following ovalbumin challenge of guinea pigs passively sensitized with homocytotropic antibodies. Simultaneously, such cells showed mitochondrial swelling with a clear matrix and partially disrupted cristae. Although a decreased number of mast cell granules generally accompanied these observations, the degree of degranulation and the morphologic appearance of the granules are less reliable criteria to indicate the immediate participation of a cell in the anaphylactic phenomenon. The cells that presented intranuclear microtubules were mainly found in the vicinity of the bronchiolar smooth muscle. The distribution of cations has been investigated in these tissues with a combined oxalate-pyroantimonate method. Whereas in controls the reaction product is located mainly in the nucleus and the mitochondria of mast cells, these sites become almost completely devoid of precipitate during the anaphylactic reaction. A hypothetical link between histamine release, intracellular distribution of cations, possibly calcium, and the appearance of intranuclear microtubules in mast cells is proposed.     

The influence of cyclic nucleotides on histamine release from lungs and on the histamine-induced contraction of guinea pig ileum

Conclusion In conclusion, exogenous cAMP and cGMP exert certain opposite actions on antibody-induced histamine release from guinea pig lungs as well as on histamine or antigen-induced contraction of guinea pig ileum smooth muscle.     

Inhalation of Cow's Milk by Sensitized Guinea Pigs in the Conscious and Anaesthetized State

Introduction of 1 ml. of cow's milk proteins, in the soluble or insoluble form, into the respiratory tract of conscious normal guinea pigs produced negligible clinical effects. In animals sensitized to milk proteins similar treatment produced severe typical anaphylactic reactions and in some animals caused rapid death.

In unsensitized guinea pigs, lightly anaesthetized to simulate sleep, similar administration of milk was without significant effect, but the inhalation of cow's milk by lightly anaesthetized sensitized guinea pigs resulted in an arrest of respiration and many of the animals died quietly without any struggle or excitement. The lungs of these animals did not show the acute emphysema characteristic of anaphylactic shock.

The experimental results are presented in support of the hypothesis that `cot death' in the human infant may be caused by a hypersensitivity reaction consequent on the inhalation of cow's milk proteins regurgitated from the stomach during sleep.

     

Inhibitory effect of anaphylactic shock by caffeine in rats

Caffeine is known to reduce evoked histamine secretion, but the effects of caffeine on anaphylactic shock have not been clarified. We have investigated the effects of caffeine on anaphylactic shock in rats. Systemic anaphylactic shock by compound 48/80 injection was monitored for 1 h. An IgE-dependent local anaphylactic shock was generated by sensitizing the skin with anti-dinitrophenyl (DNP) IgE followed 48 h later with an injection of antigen. Caffeine inhibited compound 48/80-induced anaphylatic shock to 40% with a dose of 1 mg/kg. Caffeine (0.1 mg/kg) inhibited to 56.4+/-0.4% passive cutaneous anaphylactic shock activated by anti-DNP IgE. Caffeine (5-20 mM) significantly inhibited histamine release from rat peritoneal mast cells (RPMCs) activated by compound 48/80 or anti-DNP IgE. Especially, caffeine (20 mM) inhibited by 96.7+/-0.5% histamine release activated by compound 48/80. Moreover, caffeine (1-20 mM) had a significant inhibitory effect on anti-DNP IgE-induced tumor necrosis factor-alpha production from RPMCs. The level of cAMP in RPMCs, when caffeine (20 mM) was added, increased significantly after 5-60 min compared with that of a normal control. These results indicate that caffeine inhibits immediate-type allergic reactions by inhibition of mast cell degranulation in vivo and in vitro.     

Species and tissue differences of histamine storage and release

Histamine release by compound 48/80 was studiedin vivo andin vitro in different tissues of the cat and rat. A good correlation was found between both kinds of experiment. The histamine stores in the cat salivary gland are poorly sensitive to this histamine-liberating substance.In vitro studies with heart and lungs of the rat and guinea pig showed no correlation between the spontaneous histamine release and the release induced by compound 48/80. This finding suggests the existence of two pools of tissue histamine, both with different storage and release properties, and most probably with different functions in the body.     

Studies on the biosynthesis of leukotrienes in guinea pig lung in vitro by use of high-performance liquid chromatography

The biosynthesis of leukotrienes (LTs) and 5-hydroxy-6,8,-11,14(E,Z,Z,Z)-eicosatetraenoic acid (5-HETE) in perfused guinea pig lung was studied by reversed phase-high-performance liquid chromatography (RP-HPLC). Perfusion of lungs with a 20 microM solution of ionophore A23187 for 25 minutes induced a sustained release of 5S-hydroxy-6R-S-cysteinylglycyl-7,9,11,14-(E,E,Z,Z)-eicosatetraenoic acid (LTD4) and 5S,12R-dihydroxy-6,8,10,14(Z,E,E,Z)-eicosatetraenoic acid (LTB4). The perfusion of 60 microM of arachidonic acid together with the ionophore only slightly increased the synthesis of LTD4 and LTB4 in comparison with the effect of the ionophore alone but markedly stimulated the release of 5-HETE that was not detectable under other experimental conditions. Immunologic challenge of the lung by continuous perfusion of ovalbumin to previously sensitized guinea pigs induced the release of 50 to 150 pM of LTB4 and 15 to 50 pM of LTD4 during a 25-minute period. Antigen was a less potent stimulus than the ionophore that caused the release of 500 to 900 pM of LTB4 and 100 to 250 pM of LTD4 during 25-minutes of perfusion. None of the above-mentioned metabolites were detected when lungs were perfused with arachidonic acid alone, indicating that the synthesis of 5-lipoxygenase products required activation of the lung. In addition to 5-lipoxygenase products, the cyclooxygenase products 12-hydroxy-5,8,10-(Z,E,E)-heptadecatrienoic acid and 12-keto-5,8,10-(Z,E,E)-heptadecatrienoic acid were analyzed by RP-HPLC in guinea pig lung perfusates. HPLC analysis provided quantitative data on the release of several arachidonic acid metabolites by lungs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in guanase activity in the lungs and serum of guinea pigs with anaphylactic shock

The guanase activity of the lung tissue and blood serum of guinea pigs is increased after anaphylactic shock.Presented by Academician of the Academy of Medical Sciences of the USSR S. E. Severin.Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 70, No. 12, pp. 22–23, December, 1970.     

Effect of catecholamines and sympatholytics on survival and circulatory parameters in protracted anaphylactic shock of guinea pigs.

Protracted anaphylactic shock of guinea pigs led to death in over 90% of the animals, and good protection was obtained with an infusion of adrenaline after dibenamine pretreatment. Adrenaline alone, in doses which prevented the anaphylactic fall of arterial blood pressure, had no beneficial effect. Practolol abolished the therapeutic action of the combination of dibenamine/adrenaline. Stimulation of beta-receptors by isoproterenol did not increase the survival rate. With dopamine, however, a significant prolongation of the survival times was obtained.     

A device and a method for measurement for pulmonary ventilation in small animals

Summary A method of anaphylaxis with desensitization was used to show on guinea pigs the presence of sex-linked antigens in the kidney and liver tissues of male mice (C57BL inbred strain). In the majority of the guinea pigs there occurred anaphylactic shock symptoms in response to the injection of the antigen of male mice. Tissues of female mice caused no distinct anaphylactic shock symptoms in guinea pigs in the same experimental conditions. Since a number of guinea pigs exhibited a weak anaphylactic reaction evidently female tissues also contained antigens specific to the female organism, but in low quantities.(Presented by Active Member AMN SSSR, N. N. Zhukov-Verezhnikov) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 54, No. 10, pp. 114–117, October, 1962