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Phosphodiesterases in Asthma

  • Chapter
Anti-Inflammatory Drugs in Asthma

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Airway obstruction and hyperreactivity in asthma are mainly caused by accumulation of inflammatory cells and their mediators promoting bronchoconstriction, airway oedema and airway remodeling. Cyclic AMP counteracts a huge variety of inflammatory cell functions involved in the development and maintenance of asthma. In addition, cyclic AMP has been shown to reverse bronchial constriction, airway oedema and smooth muscle proliferation and may therefore protect against airway remodeling in asthma. cAMP is generated from ATP by adenylate cyclases that are activated by G-protein coupled receptors such as the β2-receptor. In fact, attenuating cAMP generation may aggravate clinical asthma as reported with β2-antagonists. On the other hand, there is overwhelming evidence that β2-agonists improve asthma. However, long-term administration of β2-agonists may be hampered by the phenomenon of tachyphylaxis, e.g. receptor desensitization and post-receptor events. In particular, it was repeatedly demonstrated that continuous use of inhaled β2-agonists is associated with an impairment of their acute protective effects against bronchoconstrictive stimuli [1–4]. Continuous inhalation of β2-agonists impaired their bronchoprotective effect against AMP-induced hyperreactivity to a greater extent compared to hyperreactivity triggered by methacholine. These results may imply that β2-agonists tend to desensitize mast cell responses more strongly than direct smooth muscle responses [4]. Apart from enhanced cAMP generation another option to increase cAMP is to inhibit its decay. Cyclic nucleotide hydrolysing phosphodiesterases (PDE) represent a superfamily of enzymes which break down cAMP and cGMP. Thus PDE inhibitors should increase cAMP in bronchial smooth muscle and inflammatory cells and have anti-asthmatic effects.

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Tenor, H., Schudt, C. (1999). Phosphodiesterases in Asthma. In: Sampson, A.P., Church, M.K. (eds) Anti-Inflammatory Drugs in Asthma. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8751-9_3

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