Andor Szentivanyi

The beta adrenergic theory of the atopic abnormality in bronchial asthma

I n 1931, one of the founding fathers of American allergy research, Francis M. Rackemann, wrote the following lines: “The situation is somewhat analogous to that of a loaded gun. A good deal of knowledge is being obtajned about the great variety of triggers (extrinsic and intrinsic causes) which fire the charge; but why is the gun loaded? And what constitutes this load?“1 These questions refer to the fact that only a minority of the total population shows some form of atopic hypersensitivity despite that, by and large, identical conditions of antigenie exposure must be presumed to exist for all members of the same population. 2l 3 The nature of the atopic abnormality in bronchial asthma (or in any other manifestation of atopic allergy), which determines that only a relatively confined segment of a given population shows asthmatic reactivity, i.e., is affected pathologically, is as yet unexplained, but ithas been traditionally approached through immunological concepts. These concepts derive from an association of a physiochemically and biologically distinct antibody, the reagin, with this disorder, and the production and unusual reactivity of this type of antibody is thought to account for the atopic abnormality in asthma. * However, as has been extensively discussed,5 immunological concepts cannot easily account for some of t,he significant facts surrounding this disease. Therefore, based on model experiments and other considerations, an alternative to the classical concept, which came to be known as the bet,a adrenergic

Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes

Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that inactivate intracellular cyclic AMP (cAMP). Because the functions of T-lymphocytes are modulated by cAMP levels, the isozymes of PDE in these cells are potential targets for new drugs designed to modify the bodys immunity through selective alteration of T-lymphocyte PDE activity. Cyclic GMP and 3(2H)-pyridazinone-4,5- dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-monohydrochloride (CI-930) selectively inhibit the catalytic activity of one of the two high affinity cAMP-PDE isozyme families known to occur in mammals, whereas d,l-1,4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone (Ro 20-1724) selectively inhibits the other. The objectives of this investigation were: (1) to determine whether human T-lymphocytes contain one or both of these pharmacologically distinguishable high-affinity cAMP-PDEs, and (2) to determine the effects of selective inhibitors of these PDEs on lymphocyte blastogenesis. High-affinity cAMP-PDE was found in both the soluble and particulate fractions of T-lymphocyte sonicates. Cyclic GMP and CI-930 inhibited PDE in the particulate fraction better than in the soluble fraction, but the converse was found for Ro 20-1724. CI-930 or Ro 20-1724, used alone, attenuated T-lymphocyte blastogenesis, but neither suppressed it completely. In combination, the same PDE inhibitors caused greater suppression of blastogenesis than either produced alone. The results indicate that human T-lymphocytes contain both CI-930- and Ro 20-1724-inhibitable isozymes. Either of the isozymes can modulate human T-lymphocyte blastogenesis, but inhibition of both isozymes produces synergistic antiblastogenic effects.

INHIBITION OF HUMAN PULMONARY PHOSPHODIESTERASE ACTIVITY BY THERAPEUTIC LEVELS OF THEOPHYLLINE

1. To test the hypothesis that inhibition of cyclic nucleotide phosphodiesterase is the major mechanism of the bronchodilator action of theophylline in reversible airways disease, the effects of therapeutic plasma levels of the drug on human pulmonary phosphodiesterase activity were examined.

Effects of the toxin of red tide, Ptychodiscus brevis, on canine tracheal smooth muscle: a possible new asthma-triggering mechanism

The red tide toxin produced by Ptychodiscus brevis becomes airborne by the thrashing action of the surf and wind and induces cough, rhinorrhea, watery eyes, and sneezing in normal humans and wheezing in asthmatic patients. The mechanism of the contractile response induced by P. brevis toxin (PBTX) was investigated with isolated canine tracheal smooth muscle. Tetrodotoxin and atropine blocked the contractile effect of PBTX, and neostigmine potentiated the contraction. Mepyramine, phentolamine, methysergide, and chlorisondamine did not inhibit the effect of PBTX. This is the first description of a naturally occurring airborne substance that causes smooth muscle contraction by stimulating the axon sodium channels, resulting in the release of acetylcholine at postganglionic parasympathetic efferent nerve endings. The in vitro effect of PBTX on canine tracheal smooth muscle indicates that PBTX is capable of causing respiratory irritation and thus may precipitate an asthmatic attack. It is possible, however, that the mechanism is vivo may also include stimulation of a cough receptor reflex and/or stimulation of sodium channels of afferent vagus nerve fibers. In vitro evidence suggests that isoproterenol, atropine, and verapamil may be used to eliminate or prevent the respiratory symptoms that follow exposure to airborne red tide toxin. The use of high-pressure liquid chromatography separated fractions indicates that the neurotoxic component, not the hemolytic component, is responsible for contractions.

Effects of phenobarbital and 3-methylcholanthrene pretreatment on the plasma half-life and urinary excretion profile of theophylline and its metabolites in rats

Abstract The effects of the inducers of the hepatic microsomal enzyme system, phenobarbital and 3-methylcholanthrene, on theophylline plasma half-life and on the elimination of theophylline and its metabolites in urine and feces have been examined. The results indicate that induction of the hepatic microsomal drug-metabolizing enzyme system significantly decreases plasma theophylline half-life. In this respect, 3-methylcholanthrene was more effective than phenobarbital. Control theophylline half-life was 3.5 hr. After phenobarbital or 3-methylcholanthrene pretreatment, the theophylline half-life was 2.6 and 0.8 hr respectively. Thin-layer Chromatographie analysis of the urine showed three radioactive peaks corresponding to 1,3-dimethyluric acid, 1-methyluric acid and unchanged theophylline. Both inducing agents significantly increased the urinary elimination of 1,3-dimethyluric acid above that seen in control animals throughout the 24-hr collection period, but only 3-methylcholanthrene increased the total amounts of 1-methyluric acid excreted. Urinary elimination of unchanged theophylline was decreased from control values by both agents. A small, but not statistically significant, increase in the fecal elimination of radioactive material was also noted in the animals pretreated with phenobarbital. The results indicate that alteration in hepatic drug-metabolizing activity may markedly affect the in vivo biotransformation of theophylline.

The absence of adrenaline-induced hyperglycemia in pertussis-sensitized mice and its relation to histamine and serotonin hypersensitivity☆

Abstract Experiments are described which were designed to investigate the nature of the absence of adrenaline-induced hyperglycemia in pertussis-sensitized mice and its relation to histamine and serotonin hypersensitivity. It is shown that the absence of hyperglycemia after administration of adrenaline cannot be attributed to an inverse glycemic action of excessive amounts of adrenaline liberated endogenously by histamine or serotonin. On the other hand, several observations do suggest that a blockade or some other malfunctioning of the adrenergic receptors (beta), normally associated with the peripheral inhibition of glucose uptake, is responsible for the absence of hyperglycemia. This is indicated by the unusually augmented glucose tolerance of pertussis-sensitized mice, by the increased incorporation of radioactive glucose into the tissue glycogen of such animals, and by the failure of adrenaline to correct this abnormality. Furthermore, the establishment of a β-adrenergic blockade (DCI) affected the glucose tolerance of normal animals in a manner similar to pertussis sensitization, whereas an α-adrenergic blockade (Dibenamine) did not alter the normal tolerance to glucose. Although the pertussis-sensitized animals showed a normal resistance to insulin, the abnormally increased peripheral uptake of glucose in such animals is likely to be operative in the induction of hypersensitivity to histamine and serotonin. This is indicated by the fact that both alloxan diabetes and long-term, as well as acute, administration of glucose were found to restore the normal resistance of the pertussis-sensitized mouse to serotonin. Conversely, insulin was shown to sensitize normal mice to histamine and serotonin.

Characteristics of histamine tachyphylaxis in canine tracheal smooth muscle

SummaryIn isolated canine tracheal smooth muscle, repeated administrations of histamine result in a rapid reduction in contractile response to about 15% of the initial contraction (tachyphylaxis). Development of this tachyphylaxis is specific inasmuch as: 1) it does not develop to acetylcholine (10−6 M or 10−4 M), or serotonin (10−5 M); and 2) maximally developed histamine tachyphylaxis is not associated with a parallel reduction in response to acetylcholine. Pretreatment with propranolol (10−5 M) or phentolamine (10−4 M) does not prevent tachyphylaxis: however, pretreatment with atropine (10−4 M) does prevent tachyphylaxis in about 50% of the animals tested.Tachyphylaxis to histamine can be reversed in a dose- and time-dependent fashion with prostaglandin synthesis inhibiting agents. The order of potency obtained with such compounds (indomethacin > mefenamic acid > oxyphenbutazone > acetylsalicylic acid) is consistent with potencies for inhibition of prostaglandin synthesis found in the literature. Also, in indomethacin pretreated strips in which tachyphylaxis to histamine was prevented, exogenous addition of PGE2 (1.42×10−10 M to 2.84×10−9 M) and PGA2 in a high concentration (2.9×10−9 M) are capable of selectively reducing the response to histamine without an effect on acetylcholine-induced contractions. These data suggest that the mechanism of histamine tachyphylaxis in the canine tracheal smooth muscle preparation involves prostaglandin synthesis.

Modulation of endothelin-1 production by a pulmonary epithelial cell line: I. Regulation by glucocorticoids

Endothelin-1 (ET-1) is one of the most potent bronchoconstrictor agents yet described. Bronchial epithelial cells of asthmatic patients in vivo express preproET-1 and in vitro release high amounts of ET-1. Healthy and chronic bronchitic controls do not express preproET-1 or release ET-1. Interleukin-2 (IL-2) and other cytokines up-regulate the in vitro ET-1 release in guinea pig airway epithelial cells. We explored whether two glucocorticoids, dexamethasone (Dex) and triamcinolone acetonide (TA), inhibit the synthesis and release of ET-1 by A549 cells, a transformed human pulmonary epithelial cell line, since ET-1 may have a basic role in the pathogenesis of asthma. Cells were grown to confluence in RPMI 1640 plus 10% fetal bovine serum (FBS). Cells were then cultured for 3 days without serum to obtain ET-1 basal levels. The effects of 10% FBS, IL-2 (10 U/mL), Dex, TA or mifepristone, a steroid antagonist (1, 10 or 100 nM), were evaluated on ET-1 as measured by radioimmunoassay (RIA). ET-1 production increased from 57.6 +/- 5 pg/mg cell protein at 6 hr to 170 +/- 9 pg/mg cell protein at 72 hr in control cultures. Ten percent FBS increased ET-1 production from 58.7 +/- 9.6 to 399 +/- 14.5 pg/mg cell protein. IL-2 significantly increased ET-1 from 100.7 +/- 6.1 to 144 +/- 6.7 at 24 hr and from 170 +/- 9 to 207.7 +/- 24 at 72 hr. Dex and TA (10 and 100 nM) at 24-72 hr decreased ET-1 under basal conditions. Both drugs (only at 100 nM) decreased ET-1 production in 10% FBS- and IL-2-stimulated cells. Mifepristone (10 and 100 nM) reversed the decreased production of ET-1 induced by Dex (100 nM) at 24-72 hr. Northern blot analysis showed that Dex (100 nM) decreased the expression of ET-1 mRNA at 6 and 24 hr, but that mifepristone (100 nM) reversed this effect in cells cultured with Dex. In conclusion, Dex and TA down-regulate the synthesis and production of ET-1 by this human pulmonary epithelial cell line under basal or stimulated conditions, and these effects are reversed by mifepristone. These findings suggest a novel mechanism of glucocorticoid effect during the treatment of asthma.

High pressure liquid chromatography of cyclic nucleotide phosphodiesterase from purified human T-lymphocytes

The cyclic nucleotide phosphodiesterase (EC 3.1.4.17) in extracts of purified human peripheral blood T-lymphocytes was examined by ion exchange high pressure liquid chromatography. Four peaks of activity were isolated. The first peak of activity selectively hydrolyzed cyclic GMP. The following 3 peaks of activity (Ia, IIa and IIIa) were selective for cyclic AMP. The selective low Km cyclic AMP-phosphodiesterase inhibitor, Ro 20-1724 (d,1-1,4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone), did not inhibit the activity in Ia whereas it did inhibit the activity in IIa and IIIa (IC50 = 17 microM). The authors conclude that ion exchange high pressure liquid chromatography described in this communication is a useful method for the isolation of different forms of cyclic nucleotide phosphodiesterase activity from human T-lymphocytes.

Concluding Remarks and Future Directions

ABSTRACT It is indicated by this volume that normal age related changes in the neuroimmune regulatory network are highly relevant to “successful”, or healthy ageing. Abnormal regulation is associated with age related diseases. Clinical observations provide compelling evidence for the relevance of Neuroimmune Biology (NIB) to practical Medicine. Thus the Science of NIB provides novel perspectives for the investigation of highly complex biological processes, such as ageing and lead to original observations that allows for better understanding of higher organisms in their entire complexity. The future is very challenging both scientifically and from the moral standpoint.