No abstract is provided for this article.
Summary Interleukin‐5 (IL‐5) is a T helper type 2 cytokine, which is implicated in the pathogenesis of eosinophilic diseases such as asthma. Both peripheral blood mononuclear cells (PBMC) and primary human T cells display similar patterns of IL‐5 expression when stimulated with both phorbol‐12‐myristate 13‐acetate and phytohaemagglutinin. The expression of IL‐5 stimulated by these agents was shown to require de novo transcription and translation. However, although dexamethasone was a potent inhibitor of both IL‐5 release and messenger RNA accumulation from PBMC and T cells, dexamethasone had no effect on the luciferase activity of a reporter construct under the control of an IL‐5 promoter region transiently transfected into primary human T cells. Furthermore, dexamethasone appeared to decrease the stability of IL‐5 messenger RNA and this effect was dependent upon de novo transcription. Taken together, the results presented here suggest that, whilst transcriptional processes predominantly regulate IL‐5 release, the mechanism by which dexamethasone inhibits IL‐5 is post‐transcriptional.
It has been suggested that there is a preferential coupling in heart muscle between the inhibitory G protein (G i ) and the β 2 -subtype of the β-adrenergic receptor (β-AR), since pertussis toxin (which inactivates G i ) reveals latent β 2 -ARs in rat and mouse myocytes. We have previously shown that guinea pigs treated with norepinephrine (NE) for 7 days have myocytes that are desensitized to β-AR-agonist stimulation, and that pertussis toxin restores these responses. The purpose of the present investigation was to determine whether pertussis toxin specifically upregulated β 2 -ARs in myocytes from NE-treated guinea pigs. The sole β-AR subtype in control guinea pig myocytes was confirmed as β 1 -AR by radioligand binding, single-cell autoradiography, and concentration-response curves to isoproterenol in contracting myocytes. In contrast, a minor pool of β 2 -ARs was observed in rat myocytes by use of the same methods. NE treatment decreased the maximum isoproterenol response (relative to high Ca 2+ ) from 0.89 ± 0.06 to 0.58 ± 0.08 ( n = 7, P < 0.01) and the pD 2 (−log EC 50 ) from 8.8 ± 0.2 to 7.5 ± 0.2 ( n = 7, P < 0.01). Pertussis toxin treatment increased the isoproterenol-to-Ca 2+ ratio to 0.88 ± 0.04 ( n = 6, P < 0.05) and the pD 2 to 8.6 ± 0.3 ( P < 0.01). This was not mediated by increases in either number or function of β 2 -ARs. G i is therefore able to modulate β 1 -AR responses in guinea pig myocytes.
No abstract is provided for this article.
Many neuropeptides have recently been identified in human and animal airways. These peptides have potent effects on airway caliber, blood vessels, and secretions, raising the possibility that they may be involved in airway diseases such as asthma. Vasoactive intestinal peptide andpeptide histidine methionine are potent bronchodilators and may be neurotransmitters of nonadrenergic bronchodilator nerves. In asthma, if these peptides are broken down more rapidly by enzymes from inflammatory cells, this might contribute to exaggerated bronchial responsiveness. Neuropeptides that are found in sensory nerves, such as substance P, neurokinin A, and calcitonin generelated peptide, have inflammatory effects and might also contribute to the pathology of asthma if released from sensory nerve endings by an axon reflex. These findings may have important therapeutic implications for the future.
Airway caliber is determined by a balance between many constrictor and dilator agents, which bring about their effects on the various target cells of the airway by activating specific cell surface receptors. Asthma and bronchial hyperresponsiveness may be viewed as an imbalance between excitatory and inhibitory receptor-mediated effects on the various target cells in the airway. Airway receptors can be grouped into those mediating the effects of the autonomic nervous system on the airways or those mediating the effects of the various mediators which may be generated in asthma. There is no convincing evidence that a fundamental defect in receptor function is involved in the pathogenesis of asthma, although minor abnormalities have been described. Recently there has been a considerable increase in our understanding of receptor function and control, which should throw light on the pathogenesis of airway obstruction and may lead to advances in asthma therapy. This may also lead to the development of novel drugs for treating asthma in the future.
From this brief overview the arguments have become clear why further studies are needed to verify that the problem of unnecessary sudden cardiac death can best be tackled by a strategy aimed at early and complete revascularization. Whether such a strategy begins with intravenous injection of rt-PA at home or requires subsequent intracoronary manipulation when obstruction persists, whether by thrombolysis with other agents, PTCA or bypass surgery, is in itself a moot point. The main aim should be to offer this strategy as the best chance to reduce the unnecessary sudden death rate which presently accounts for between 25 and 50% of all cardiac deaths. This approach deserves consideration particularly since earlier approaches employing cardioprotective efforts by beta blockade or by anti arrhythmic agents have patently shown that they cannot tackle the problem in a convincing manner.
