Cyclic nucleotides and phosphodiesterases and airway function

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.

Section: Discussionmentioning

confidence: 46%

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

Germain

Bertin²,

Legendre³

et al. 1998

“…Activation of PKG is a well-established mechanism leading to relaxation of smooth muscle [223], including ASM [224][225][226], which may involve the direct phosphorylation and activation of BK Ca [227]. In addition, PKG can lead to the repression of certain genes that may be of potential significance in airways diseases such as asthma, of which inflammation is a characteristic feature [223,225,226]. Of particular interest is the finding that K + -induced contractions of guinea pig tracheal segments were more potently inhibited by cell permeant cGMP analogues than by analogues of cAMP [75].…”

Section: Activation Of Pkgmentioning

confidence: 99%

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

Giembycz

Newton²

2006

132

118

b 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade.This classical model of b 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of b 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by b 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMPdependent and -independent mechanisms that, in many cases, may act in concert.In this article, the current status of b 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.

“…PDE inhibitors may act synergistically with receptordependent activators of adenylyl cyclase to inhibit polymorphonuclear leucocyte activation in vitro [23][24][25]. Currently, PDE IV inhibitors are considered one of the most promising antiasthma drugs for the future [26]. In this context, the effects of these compounds on the eosinophil is of interest.…”

mentioning

confidence: 99%

Inhibition of PAF-induced expression of CD11b and shedding of L-selectin on human neutrophils and eosinophils by the type IV selective PDE inhibitor, rolipram

Berends¹,

Dijkhuizen²,

Monchy

et al. 1997

We quantitatively determined whether the selective phosphodiesterase (PDE) inhibitor, rolipram, inhibits changes in the adhesion molecules CD11b and L-selectin on platelet-activating factor (PAF)-stimulated human neutrophils and eosinophils in vitro.Incubations were performed in human whole blood obtained from healthy volunteers, to restrict activation by purification procedures and to simulate in vivo conditions, in which different cell types may interact, more closely. Receptor expression was measured after fixation of cells, using monoclonal antibodies and flow cytometry.Concentration-dependent inhibition of the PAF-induced CD11b expression and L-selectin shedding for neutrophils and eosinophils was observed with rolipram, dibutyryl cyclic adenosine monophosphate (cAMP), prostaglandin E 2 (PGE 2 ), and isoproterenol. However, these inhibitions did not exceed 50%. Preincubation with rolipram (10 -8 M) and subsequent incubation with isoproterenol (0.5×10 -8 M) or PGE 2 (10 -8 M) induced a cumulative, but not synergistic, effect. Using the combination of rolipram with isoproterenol or PGE 2 , inhibition of PAF-induced Lselectin shedding from eosinophils was as high as 71±28 and 67±21%, respectively. Other inhibitions were below 50%.In conclusion, rolipram inhibits CD11b expression and L-selectin shedding of platelet-activating factor-stimulated neutrophils and eosinophils in whole blood in a concentration-dependent fashion. Inhibitions did not exceed 50%, even at high concentrations. The inhibition of platelet-activating factor induced shedding of Lselectin from eosinophils with a combination of rolipram and prostaglandin E 2 or isoproterenol, however, was found to be approximately 70%. Inhibition of rolling adhesion of eosinophils may, therefore, be a mode of action of type IV phosphodiesterase inhibitors.