Selective phosphodiesterase inhibitors modulate the activity of alveolar macrophages from sensitized guinea-pigs

Abstract

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.

Reduced Airway Hyperresponsiveness by Phosphodiesterase 3 and 4 Inhibitors in Guinea‐Pigs

“…In this regard, w e observe d that the c ombination of milrinone and the sele ctive PDE4 inhibitors, rolipram or Ro 20 -1724 had a signific ant inhibitory effe ct on arachidonate re le ase. 9 We rec ently proposed that the reduced activity of alve olar macrophage s may be involved in the inhibition of the de ve lopme nt of airw ay hype rresponsiveness by both PDE3 and PDE4 inhibitors and suggest that activation of alveolar macrophage s is a ke y e vent in the bronchopulmonary alterations that follow antige n challenge.…”

“…9 ,17 ,1 8 We have also reported that mac rophages recove red in the BAL fluid of e ithe r saline-ex posed or OA-challenge d se nsitized guinea-pigs ex hibit a PDE type 3 and a PDE type 4 is oe nzyme activity. 9 It c an there fore be suggeste d that the p rofile of PDE activities in mac rophage s may influe nce the ac tivity of PDE inhibitors. In this regard, w e observe d that the c ombination of milrinone and the sele ctive PDE4 inhibitors, rolipram or Ro 20 -1724 had a signific ant inhibitory effe ct on arachidonate re le ase.…”

“…8 We also re c ently demonstrated that PDE3 and PDE4 isoenzymes are present in alveolar mac rophage s from sensitized guinea-pigs and that PDE4, but also PDE3, regulate the re lease of inflammatory me diators. 9 Numerous studie s have reported the ac tual efficacy of PDE inhibitors, name ly selective PDE4 inhibitor s, on the development of airw ay hyperresponsiveness. How ever the effects of PDE3 inhibitors appe ar controversial.…”

Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

“…Previous work has shown that PDE3 and PDE4 are the primary isoforms expressed in AMs [16]; therefore, we chose to examine the relative gene expression of each of these enzymes in AMs from young (day 7 and 14) compared to adult AMs (Figure 3B). There was no difference in the expression of PDE4A, PDE4B, or PDE4D between the young and the adult AMs (Figure 3B).…”

Simultaneous determination of YM‐64227, a phosphodiesterase type 4 inhibitor, and its five metabolites in dog plasma by high‐performance liquid chromatography with fluorescence detection

“…Among these enzymes, phosphodiesterase type 4 (PDE4) is a high-affinity cAMP-selective isozyme (Beavo, 1995). The inhibition of PDE4 relaxes airway smooth muscle (Torphy et al, 1988;Harris et al, 1989;Shahid et al, 1991;Heaslip et al, 1994) and induces anti-inflammatory effects, such as the reduction of chemical mediator released from mast cells (Weston et al, 1997), basophils (Peachell et al, 1992;Weston et al, 1997), eosinophils (Dent et al, 1991;Underwood et al, 1993Underwood et al, , 1994Raeburn et al, 1994) and macrophages (Germain et al, 1998;Goncalves de Moraes et al, 1998). As a result, PDE4 inhibitors 668 D. Tenmizu et al ORIGINAL RESEARCH In vivo and in vitro metabolism studies demonstrated that YM-64227 is biotransformed into five hydroxylated metabolites which also inhibit PDE4 activities.…”