Monocyte Phosphodiesterase Abnormalities and Dysregulation of Lymphoctye Function in Atopic Dermatitis.

Hanifin, John M.; Chan, Sai C.

doi:10.1111/1523-1747.ep12316116

Cited by 34 publications

(18 citation statements)

References 36 publications

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“…Indeed, Hanifin et al (43) have proposed that expression of an activated PDE and the consequent decrease in cAMP in inflammatory cells may result in hyperreactivity and that this condition may be inherited. This is certainly possible in the PDE4 proteins, for it has been demonstrated that PDE4s exist in several conformations that affect the activity of the catalytic domain (44), and point mutations in a phosphorylation site of PDE4D yield a constitutively active enzyme (13).…”

Section: Discussionmentioning

confidence: 99%

Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D

Hansen

Jin

Umetsu

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

155

129

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Muscarinic cholinergic signaling plays an essential role in the control of the normal airway functions and in the development of pulmonary pathologies including asthma. In this paper we demonstrate that the airways of mice deficient in a cAMP-specific phosphodiesterase (PDE4D) are no longer responsive to cholinergic stimulation. Airway hyperreactivity that follows exposure to antigen was also abolished in PDE4D ؊/؊ mice, despite an apparently normal lung inflammatory infiltration. The loss of cholinergic responsiveness was specific to the airway, not observed in the heart, and was associated with a loss of signaling through muscarinic receptors with an inability to decrease cAMP accumulation. These findings demonstrate that the PDE4D gene plays an essential role in cAMP homeostasis and cholinergic stimulation of the airway, and in the development of hyperreactivity. In view of the therapeutic potentials of PDE4 inhibitors, our findings provide the rationale for novel strategies that target a single PDE isoenzyme.

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Section: Discussionmentioning

confidence: 99%

Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D

Hansen

Jin

Umetsu

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

155

129

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“…As a significant increase in PDE4 activity has been reported in patients with asthma or allergy compared with healthy individuals [12,13], it is therefore of interest to explore PDE4 inhibition as a potential therapeutic option for treatment of atopic asthma, given the proposed anti-inflammatory mode of action [14]. …”

Section: Introductionmentioning

confidence: 99%

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

et al. 2011

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BackgroundPhosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.Methods25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.ResultsRoflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.ConclusionsThis study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.Trial RegistrationClinicalTrials.gov: NCT01365533

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“…11 Dermatotherapeutic Agentsfever or asthma. The underlying cause is not known, but it may be related to alteration in cellular and humoral immunity mediated by cyclic nucleotides or to autonomic nervous system function [11].…”

Section: Anti-inflammatory Agentsmentioning

confidence: 99%

“…Many of the theraVol. 11 Dermatotherapeutic Agentspeutic modalities for severe psoriasis (photochemotherapy, phototherapy, and cytotoxic therapy) directly suppress immune cell activity. Some of these agents also diminish epidermal hyperplasia by inhibiting DNA synthesis and mitosis.…”

Section: Antipsoriaticsmentioning

confidence: 99%

Dermatotherapeutic Agents

Gendimenico

2006

Ullmann's Encyclopedia of Industrial Chemistry

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Monocyte Phosphodiesterase Abnormalities and Dysregulation of Lymphoctye Function in Atopic Dermatitis.

Cited by 34 publications

References 36 publications

Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D

Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

Dermatotherapeutic Agents

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