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PubMedDate not supplied

[Mediators of the allergic reaction. Slow reacting substance (SRS-A)].

The slow reacting substance of anaphylaxis (SRS-A) belongs to a group of substances which produce a slow progressive and sustained contraction of some smooth muscles. It is released by the interaction of the antigen with certain antibodies; in humans through the interaction with the IgE or reagine. The SRS-A is a heat-labile sustance, chemically unstable, of an acid character, with a low molecular weight. It is not destroyed by the action of proteolytic enzymes. Its molecular structure has not yet been elucidated. It is not found accumulated in the cells but synthesized and released by some white cells mainly by sensitized mast cells and polymorphonuclear leukocytes after challenging with the specific antigen. The SRS-A is a powerful pharmacodynamic agent, it produces contraction of the bronchial smooth muscle in doses of nanograms. It probably plays a predominant role in the physiopathology of asthma. The chain of chemical reactions elicited by antigen-antibody interaction does not end with the release of SRS-A and the other mediators (histamine, eosinophil chemotactic factor of anaphylaxis, ECF-A), on the contrary, these mediators especially SRS-A induce the release of prostaglandins of type E (PGE1 and PGE2) which produce bronchodilatation and inhibit the release of SRS-A itself, perhaps being a selfregulating mechanism. The PGF2a, on the other hand, produces bronchoconstriction. The release of SRS-A is also inhibited by the action of diethyl-carbamazine and especially by sodium chromoglicate and compound AH-7725. From the biochemical point of view it is found that the antigen Igells, a serine esterase, initiating several chemical reactions whose consequence is a decrease in the cAMP concentration. This reduction in the cAMP intracellular level is followed by synthesis and excretion of the SRS-A as well as by the aggregation of the microtubules and excretion of the stored histamine. The PGE (1 and 2) acting on one type of membrane receptor and the beta-agonist catecholamines on another produce a common phenomenon: the activation of the adenylcyclase whcih produces the increase of the concentration of cAMP and inhibits the release of mediators of the anapylactic reaction. The parasympathetic system through its chemical mediator acethylcholine, by a mechanism in whcih adenycyclase is not involved is also capable of stimulating the release of histamine and SRS-A. Something similar happens with PGF2a. In conclusion, self-regulatory mechansims for the release of mediators of the anaphylactic reactions may exist. The "perpetuation" of an asthamtic reaction would signify a failure of these self-regulatory mechanisms due to, for example, to a temporary block of the beta-adrenergic receptors, overstimulation of the alfa-receptors or insufficient production of PGE or a transformation of the PGE in PGF.

Adrenergic beta-Antagonists↗
PubMed1976

Separation of slow reacting substance of anaphylaxis (SRS-A) from human lung into four biologically active fractions.

Slow reacting substance of anaphylaxis (SRS-A) was released from human lung passively sensitized with ragweed antibody and challenged with specific antigen E. After purification by ethanol extraction, incubation with alkali (0.1 M NaOH for 30 min at 37 degrees C) and chromatography on silicic acid and DEAE-cellulose, human SRS-A was separated into four biologically active fractions (Fractions I to IV). Arylsulfatase (Type H-1) in 0.1 M sodium acetate buffer, pH 4.5, destroyed the biologic activity of only Fraction I. All four fractions, like SO4=, inhibited the arylsulfatase activity at pH 4.5 but not at pH 6.0 when p-nitrocatechol sulfate was used as substrate. These results suggest that SRS-A contain a sulfur group and that human STS-A, like the prostaglandins, may be a family of compounds. The instability of the purified SRS-A to storage remains a major barrier to their further purification and chemical identification.

Arylsulfatases↗
PubMed1976

Slow reacting substance as a preformed mediator from human lung.

Homogenates from human lung contained a preformed slow reacting substance (pSRS). The pattern of contraction on the guinea-pig ileum by pSRS was indistinguishable from that of SRS-A. The activity of pSRS could not be attributed to the presence of K+, Na+, Ca2+ and Mg2+ ions, or any prostaglandin including PGF2 or its 15-oxo derivative. As with SRS-A, pSRS could be absorbed onto Amberlite XAD-2 and silicic acid. Both were eluted from the former with 80 per cent ethanol and from the latter with a mixture of ethanol, ammonia and water. Both pSRS and SRS-A were resistant to the action of NaOH whereas their activities were destroyed by boiling in HCl. Arylsulphatase II B destroyed the activities of both pSRS and SRS-A. An antagonist of SRS-A, FPL55712, inhibited the action of pSRS at comparable concentrations to that of SRS-A. These experiments suggest that pSRS and SRS-A are identical. Thus SRS joins histamine and ECF-A as a preformed mediator. Although SRS was present in a preformed state the amount of material extractable was more than doubled by the anaphylactic reaction. The extraction of slow reacting substance from human lung without apparent requirement for antigen or antibody points to a possible role of this mediator in inflammatory reactions evoked by mechanisms independent of IgE and other tissue-sensitizing antibodies.

Antigens↗
PubMed1978

Stimulation of arachidonic acid metabolism by human slow-reacting substances.

Human slow-reacting substance of anaphylaxis (SRS-A) and calcium ionophore-induced human SRS released prostaglandin-like substances and rabbit aorta contracting substance (RCS) from guinea-pig lungs. This effect was abolished by incubation of SRS-A and SRS with arylsulphatase or pretreatment of the lungs with indomethacin. Human SRS-A and SRS therefore resembled guinea-pig SRS-A in stimulating arachidonic acid metabolism. These results provide further evidence for a similar (or identical) nature of human SRS-A and SRS and suggest a possible role for slow-reacting substances in the release of prostaglandins during anaphylaxis.

Animals↗
PubMed1976

Arylsulfatase B of human lung. Isolation, characterization, and interaction with slow-reacting substance of anaphylaxis.

Arylsulfatase B was separated from arylsulfatase A in extracts of human lung tissue by anion exchange chromatography and further purified by gel filtration and cation exchange chromatography. Arylsulfatase B of human lung was similar to that enzyme in other tissues and species, exhibiting an apparent mol wt of approximately 60,000, a pH optimum for cleavage of 4-nitrocatechol sulfate (pNCS) of 5.5-6.0, and a sensitivity to inhibition by phosphate ions and especially pyrophosphate in the presence of NaCl. Human lung arylsulfatase B inactivated slow-reacting substance of anaphylaxix (SRS-A) in a linear time-dependent reaction in which the rate was determined by the enzyme-to-substrate ratio. Cleavage of pNCS by human lung arylsulfatase B was competitively suppressed by SRS-A. The finding that human lung tissue contains predominately arylsulfatase B discloses a potential regulatory mechanism for inactivation of SRS-A at or near the site of its generation.

Chondro-4-Sulfatase↗
PubMed1977

Autacoid and anaphylactic reactivity of pulmonary and hepatic smooth musculature of the cat.

Histamine, 2-methylhistamine (2-MeH: a relatively specific H1 receptor agonist), 5-HT, carbachol, bradykinin (BK) and PGF2alpha contract isolated cat pulmonary vein, artery and hepatic vein. PGE1, PGF2alpha and 4-methylhistamine (4-MeH: a relatively specific H2-receptor agonist) contract pulmonary arterial strips but further increase in the dose of PGE1 produces relaxation. Isoproterenol relaxes partially contracted blood vessels at low doses, but contracts at high doses. Cat trachea contracts to 5-HT, acetylcholine and carbachol but is insensitive to histamine, its analogues, BK and PGF2alpha. However, partially contracted trachea relaxes to histamine, 4-MeH, 2-MeH, isoprenaline, BK, PGE1, E2 and F2alpha. PGF2alpha and SRS-A contract cat bronchus. Isoprenaline, PGE1 and E2 relax cat bronchus contracted to carbachol, 5-HT, PGF2alpha, SRS-A and antigen. The in vitro anaphylactic contraction (Schultz-Dale reaction) of isolated pulmonary and hepatic veins, bronchus and trachea from horse plasma sensitized cat suggested the involvement of lung and liver in anaphylaxis of the cat.

Anaphylaxis↗
PubMed1975

In vitro antagonism of the mediators of allergy by a benzopyrano-benzopyran carboxylic acid PR-D-92-EA.

PR-D-92-EA was tested on isolated guinea pig ileum and rat stomach strips for activity against mediators probably released after allergen antibody union. It antagonized the response produced by histamine, bradykinin, serotonin, prostaglandin E2, prostaglandin F2ALPHA and slow-reacting substance of anaphylaxis (SRS-A). The concentrations which blocked 50% of the response were 150, 145, 92, 70, 47, and 32 mug/ml, respectively. This compound may be useful in the treatment of allergic conditions.

Animals↗
PubMed1977

Atypical (relaxant) response to histamine in cat bronchus.

Histamine, 2-methylhistamine (a specific H1-receptor agonist), 4-methylhistamine (a specific H2-receptor agonist), isoprenaline, bradykinin, prostaglandin E1, E2, and F 2alpha induce relaxation of carbachol-contracted isolated cat bronchial strips and tracheal chains. Bovine SRS-A contracts bronchus but not trachea. Histamine-induced relaxation of cat bronchus is not blocked by mepyramine (a specific H1-receptor antagonist); metiamide or burimamide (specific H2-receptor antagonists); propranolol ( a beta-adrenoceptor blocker) and indomethacin (a PG-synthetase inhibitor) suggesting non-participation of H1,H2-histamine receptors, beta-adrenoceptors (catecholamine release) and prostaglandin release in histamine-induced broncho-relaxations in the cat. The existence of an atypical histamine response, resistant to both H1- and H2-receptor antagonists is thus established in cat bronchus.

Airway Resistance↗
PubMed2026

Autistic-like traits and longitudinal changes in health-related quality of life among individuals with bipolar disorder: A 12-month study.

OBJECTIVE: Autistic-like traits are common in bipolar disorder (BD) and have been linked to poor functional outcomes, yet their longitudinal impact on quality of life (QOL) remains unclear. This study examined whether autistic-like traits are associated with 12-month changes in health-related QOL in BD. METHODS: Seventy-eight outpatients with BD who completed 12-month follow-up assessments were included (mean age = 34.9 years). Autistic-like traits were assessed using the Social Responsiveness Scale for Adults (SRS-A), with participants classified into elevated- and non-elevated-traits groups. Depressive and manic symptoms were evaluated using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS). QOL was measured using the 36-Item Short-Form Health Survey (SF-36). Linear mixed models were used to examine longitudinal changes. RESULTS: HAMD-17 scores demonstrated significant main effects of time and group, reflecting overall improvement but persistently higher depressive symptoms in the elevated-traits group. YMRS scores indicated a significant group effect only. Physical QOL remained stable, while mental QOL improved over time without group differences. Role/social QOL showed significant main effects of time and group, with consistently lower scores in the elevated-traits group. No group × time interactions emerged, suggesting similar rates of change between groups. CONCLUSIONS: This prospective study suggests that autistic-like traits in BD are associated with persistently poorer role/social functioning over time rather than differences in recovery trajectories. Assessing autistic-like traits may help identify patients at risk of poorer functioning and guide tailored psychosocial interventions.

Autistic-like traits↗
PubMed1976

The cat lung strip as an in vitro preparation of peripheral airways: a comparison of beta-adrenoceptor agonists, autacoids and anaphylactic challenge on the lung strip and trachea.

1 A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat. 2 The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2alpha, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2alpha and did not exhibit an intrinsic tone. 3 (-)-Isoprenaline and (-)-adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (+/-)-noradrenaline in the lung strip was isoprenaline greater than adrenaline greater than noradrenaline but in the trachea was isoprenaline greater than noradrenaline greater than or equal to adrenaline. 4 beta2-Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting beta2-adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of beta2-adrenoceptors in lung strip and beta1-adrenoceptors in trachea. 5 Strong Schultz-Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyramine-treated lung strip and trachea was not due to prostaglandins E1, F2alpha or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS-A). 6 It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.

Adrenergic beta-Agonists↗
PubMed1976

[Bronchial mediators and receptors: current data].

This is a very precise study of the mechanisms which intervene in bronchial motility. It is apparent that the most important recent acquisitions in the realm of bronchial mediators, over these last 10 years remains: the demonstration in the animal and in man of the duality between adrenergic bronchoconstriction of alpha nature and adrenergic bronchoconstriction of beta-2 nature, the duality of the effects of prostaglandins (PGF2 alpha broncho-constrictive, and PGE2 bronchodilator), and the role of cyclic AMP at the junction of the action of numerous substances which are active on the bronchial musculature.

Acetylcholine↗
PubMedDate not supplied

Experiments on the role of virus infections in the pathogenesis of bronchial asthma. The role of innate or acquired insufficiency or ergotropic adaptation in the mechanism of genesis of bronchial asthma.

UNLABELLED: The wide mosaic of congruent clinical and experimental observations led to the postulation that the cause of the pharmacological abnormality of the asthmatic patient, i.e. the immensely increased reactivity of the bronchial smooth muscles, is to be sought in an insufficiency of the beta-adrenergic receptor system. It is to be assumed that the so-called asthma diatheses is based inter alia on a genetically determined defect of the adenyl cyclase system. The role of previous infections of the respiratory tract in asthmagenesis should lie--following this working theory--not in a sensitization in the sense of an allergic reaction of the immediate type, but in the formation of a defective beta-adrenergic substance or in a blockade of the beta-receptor. A genetically determined innate defect of the beta-adrenergic receptors, or a defect acquired through infections of the respiratory tract, is hence likely to be the cause of the pathologically potentiated reactivity of the bronchia. It is likely that the infective stimuli--quite apart from this preparatory role--are later capable of triggering asthmatic paroxysms when the vegetative homeostasis is impaired. We know from the experiments of many authors that a blockade of the beta-receptors produced by chemical blocker substances, or by pertussis vaccine or various bacterial substances, results in a significant increase in bronchial reactivity towards histamine, serotonin, acetylcholine and other stimuli. We have shown in our experiments that heat-inactivated adeno viruses and influenza viruses also increase the anaphylactic shock reactivity and the histamine reactivity of the organism. On the basis of this working hypothesis, the pathomechanism of the asthmatic process is as follows in individual asthma forms: 1) In the 'purely" allergic asthma form, the antigen-antibody reaction that occurs after sensitization (i.e. formation of skin-sensitizing allergic antibodies of the class IgE) results in re-formation and release of slow-reacting-substances. RESULT: spasm of the bronchial muscles, asthmatic paroxysm. The expulsion of catecholamines that follows the release of slow-reacting-substances makes a decisive contribution to the reestablishment of the impaired homeostatic balance. It is to be assumed that this form of asthma both symptomatically and causally--using specific desensitization--can be influenced more easily than other forms of asthma with a more complicated pathogenic background. 2) In the second allergically determined form of asthma, we are confronted by the genetically fixed or acquired insufficiency of the beta-receptors in addition to the immunological mechanism. As a result of the innate or acquired blockade of the beta-receptive substance, or the relative dominance of the alpha-receptors, the catecholamines (that physiologically serve to maintain homeostasis) contribute to a protraction, intensification and perpetuation of the bronchial obstruction. In this way the asthmatic circulus vitiosus is complete...

Adenoviridae↗