The cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are important second messengers in cell function. The concentration of intracellular cAMP increases either as a consequence of receptor-triggered adenylyl cyclase activation or by decreased activity of phosphodiesterase (PDE), which regulates the breakdown of cAMP and cGMP. PDE are a growing group of enzymes, classified into seven distinct families (PDE1-PDE7) with several subtypes and splice variants (for recent reviews, see [1 , 2]). Among them, PDE3, PDE4 and PDE7 appear to be the most important in the regulation of cAMP. In the majority of inflammatory cells, the low Michaelis constant (kM) cAMP-specific members of the PDE4 family are the most prominently expressed and, thus, have attracted attention as a pharmacological target in the field of inflammatory drug development [3][4][5]. Selective PDE4 inhibitors such as rolipram and Ro 20-1724 have been shown to inhibit several leukocyte functions, including inflammatory mediatorrelease [5].In mononuclear cells, PDE3 is also involved in the regulation of cAMP levels. Indeed, the selective PDE3 inhibitor milrinone elicits a moderate inhibition of arachidonate release from these cells [6] and appears to synergize with inhibitors of PDE4 to reduce proliferation [7]. In macrophages, in the presence of the adenylyl cyclase activator, prostaglandin E2 (PGE2), PDE3 inhibitors are as effective as PDE4-selective drugs in the inhibition of tumour necrosis factor-α release [8]. Therefore, HATZELMANN et al. [9] proposed that PDE3-PDE4 synergism may reduce the risk of side-effects caused by each selective inhibitor alone, since it is plausible that the required doses of dual inhi-bitors of PDE3 and PDE4 isoenzymes will be markedly lower than those of selective inhibitors alone. Alveolar macrophages play a major role in lung defence. In addition, they are the main cell type involved in the tissue injury associated with inflammatory disease in the lung, including asthma and acute respiratory distress syndrome (for review, see [10]). Indeed, alveolar macrophages are able to release several inflammatory mediators, including cytokines, growth factor and arachidonic acid metabolites, in various pathophysiological situations (for review, see [11]). Bronchial hyperresponsiveness is associated with enhanced activity of alveolar macrophages collected from sensitized and antigen-challenged guineapigs or naive guinea-pigs exposed to an aerosol of substance P [12,13]. In conclusion, these data show that phosphodiesterase-4 isoenzyme may regulate the release of inflammatory mediators such as arachidonate from macrophages through an increase in intracellular cyclic adenosine monophosphate. This suggests that phosphodiesterase-4 inhibitors have potential in the treatment of inflammatory disorders of the lung.
