INT79456

Context Info Confidence 0.77 First Reported 1999 Last Reported 2010 Negated 1 Speculated 1 Reported most in Body Documents 35 Total Number 37 Disease Relevance 19.42 Pain Relevance 7.42

cytosol (PDE4A) signal transduction (PDE4A) plasma membrane (PDE4A) nucleus (PDE4A) cytoplasm (PDE4A)

Anatomy Link Frequency macrophages 4 smooth muscle 3 fibroblasts 3 epithelial cells 3 neutrophils 3 PDE4A (Homo sapiens)

Pain Link Frequency Relevance Heat adenocard 39 100.00 Inflammation 1208 99.76 Paracetamol 6 98.72 Nicotine 192 98.36 cINOD 34 97.64 Analgesic 1 97.12 b2 receptor 58 95.48 acular 1 93.24 cytokine 1053 92.88 agonist 199 92.32

Disease Link Frequency Relevance Heat Pulmonary Disease 1045 99.84 INFLAMMATION 1303 99.76 Asthma 1984 99.36 Overdose 4 99.08 Vasculitis 4 98.68 Disease 326 97.56 Depression 22 91.64 Eczema 24 91.24 Death 26 91.20 Rhinitis 66 90.36

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

We found that PDE4 family is the major cAMP-PDE expressed in human fetal membranes and that PDE4 activity is increased by LPS treatment.

Gene_expression (expressed) of PDE4

1) Confidence 0.77 Published 2005 Journal J. Immunol. Section Abstract Doc Link 15944316 Disease Relevance 0.71 Pain Relevance 0.45

There are four different genes encoding the cAMP-specific phosphodiesterase (PDE4) isozymes (A, B, C, and D). cAMP has been the only agent known to induce PDE4 gene expression.

Gene_expression (expression) of PDE4

2) Confidence 0.75 Published 1999 Journal Mol. Pharmacol. Section Abstract Doc Link 9882697 Disease Relevance 0 Pain Relevance 0

On this model of explants, we demonstrated that PDE4 selective inhibitors diminished greatly the production of TNF?

Gene_expression (selective) of PDE4

3) Confidence 0.66 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.41 Pain Relevance 0.25

Whilst macrophages do express PDE4 it appears that their function is poorly inhibited by PDE4 inhibitors, although the efficacy of these drugs is enhanced when used in combination with agents that raise intracellular levels of cyclic AMP (eg, prostaglandin E2) or if there is concurrent inhibition of PDE3 and PDE7 (Hatzelmann and Schudt 2001; Smith et al 2004).

Gene_expression (express) of PDE4 in macrophages

4) Confidence 0.62 Published 2007 Journal International Journal of Chronic Obstructive Pulmonary Disease Section Body Doc Link PMC2695611 Disease Relevance 0.48 Pain Relevance 0.23

An important implication of these experimental observations is that PDE4 inhibitors may only be partially effective in COPD in view of the proposed role of macrophages in this disease (Barnes and Stockley 2005) and there is therefore a case for the potential development of dual PDE inhibitors in the context of COPD (Smith et al 2004; Boswell-Smith et al 2006).

Gene_expression (effective) of PDE4 in macrophages associated with pulmonary disease and disease

5) Confidence 0.62 Published 2007 Journal International Journal of Chronic Obstructive Pulmonary Disease Section Body Doc Link PMC2695611 Disease Relevance 0.61 Pain Relevance 0.11

We examined in human myometrium the expression of the four genes of PDE4 in the nonpregnant state and near term.

Spec (examined) Gene_expression (expression) of PDE4 in myometrium

6) Confidence 0.59 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.23 Pain Relevance 0.03

We explored in parallel the molecular mechanism of the hormonal regulation of the PDE4 expression in primary culture of myometrial cells.

Gene_expression (expression) of PDE4

7) Confidence 0.59 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.08 Pain Relevance 0.16

Like in the tissue of origin, PDE4 is the major cAMP-hydrolyzing activity in these cells and the four PDE4 genes are expressed.

Gene_expression (expressed) of PDE4

8) Confidence 0.59 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.07 Pain Relevance 0.15

With the exception of the platelet, all immune and proinflammatory cells express PDE4.12 PDE4 variants are also abundant in structural cells including airway smooth muscle, epithelial cells, and fibroblasts.38 Without exception, each of these cell types coexpress multiple PDE4 variants derived from PDE4A, PDE4B, and PDE4D12 and, currently, the isoform(s) that must be inhibited for the anti-inflammatory actions of PDE4 inhibitors to be realized is largely unknown.

Gene_expression (express) of PDE4 in smooth muscle associated with inflammation

9) Confidence 0.59 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.37 Pain Relevance 0.04

Finally, total systemic exposure, estimated from the AUC, exceeds that of roflumilast by about 10-fold.59 Taken together, these data indicate that the N-oxide metabolite accounts for about 90% of the biologic action of roflumilast and produces long-lasting, competitive PDE4 inhibition over 24 hours, making once-daily roflumilast administration a realistic treatment regimen.

Gene_expression (produces) of PDE4

10) Confidence 0.59 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.13 Pain Relevance 0

With the exception of the platelet, all immune and proinflammatory cells express PDE4.12 PDE4 variants are also abundant in structural cells including airway smooth muscle, epithelial cells, and fibroblasts.38 Without exception, each of these cell types coexpress multiple PDE4 variants derived from PDE4A, PDE4B, and PDE4D12 and, currently, the isoform(s) that must be inhibited for the anti-inflammatory actions of PDE4 inhibitors to be realized is largely unknown.

Gene_expression (express) of PDE4 in smooth muscle associated with inflammation

11) Confidence 0.59 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.37 Pain Relevance 0.04

With the exception of the platelet, all immune and proinflammatory cells express PDE4.12 PDE4 variants are also abundant in structural cells including airway smooth muscle, epithelial cells, and fibroblasts.38 Without exception, each of these cell types coexpress multiple PDE4 variants derived from PDE4A, PDE4B, and PDE4D12 and, currently, the isoform(s) that must be inhibited for the anti-inflammatory actions of PDE4 inhibitors to be realized is largely unknown.

Gene_expression (coexpress) of PDE4 in smooth muscle associated with inflammation

12) Confidence 0.59 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.48 Pain Relevance 0.05

As the expression of PDE7A mirrors the distribution of PDE4 we speculate that this enzyme could be a target for novel anti-inflammatory drugs.

Gene_expression (expression) of PDE4 associated with inflammation and cinod

13) Confidence 0.55 Published 2003 Journal Am. J. Physiol. Lung Cell Mol. Physiol. Section Abstract Doc Link 12388353 Disease Relevance 0.23 Pain Relevance 0.10

PDE4 is a cyclic adenosine monophosphate (cAMP) specific enzyme, which hydrolyses cAMP to AMP and is the predominant isoenzyme expressed in macrophages, lymphocytes and neutrophils [6].

Gene_expression (expressed) of PDE4 in lymphocytes associated with adenocard

14) Confidence 0.54 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2911898 Disease Relevance 0.76 Pain Relevance 0.47

PDE4 is expressed in macrophages, neutrophils, T cells and airway smooth muscle cells [8].

Gene_expression (expressed) of PDE4 in neutrophils

15) Confidence 0.45 Published 2008 Journal J Occup Med Toxicol Section Body Doc Link PMC2259400 Disease Relevance 1.17 Pain Relevance 0.19

PDE4 subtype expression is lower and shows more intersubject variability in CD8+ cells however [54].

Gene_expression (expression) of PDE4

16) Confidence 0.45 Published 2008 Journal J Occup Med Toxicol Section Body Doc Link PMC2259400 Disease Relevance 0.58 Pain Relevance 0.17

There are no significant differences in the expression of PDE4A, PDE4B and PDE4D in peripheral blood CD4 and CD8 lymphocytes from normal and asthmatic patients [54].

Gene_expression (expression) of PDE4A in lymphocytes associated with asthma

17) Confidence 0.45 Published 2008 Journal J Occup Med Toxicol Section Body Doc Link PMC2259400 Disease Relevance 0.72 Pain Relevance 0.14

Several phosphodiesterase IV (PDE4) inhibitors induce inflammatory vascular injury in preclinical species.

Gene_expression (Several) of PDE4 associated with inflammation and vasculitis

18) Confidence 0.40 Published 2010 Journal Toxicological Sciences Section Body Doc Link PMC2923281 Disease Relevance 0.65 Pain Relevance 0.51

Several phosphodiesterase IV (PDE4) inhibitors induce inflammatory vascular injury in preclinical species.

Gene_expression (Several) of phosphodiesterase IV associated with inflammation and vasculitis

19) Confidence 0.40 Published 2010 Journal Toxicological Sciences Section Body Doc Link PMC2923281 Disease Relevance 0.65 Pain Relevance 0.51

Selective inhibitors of phosphodiesterase 4

Gene_expression (Selective) of phosphodiesterase 4

20) Confidence 0.39 Published 2008 Journal J Occup Med Toxicol Section Body Doc Link PMC2259400 Disease Relevance 1.11 Pain Relevance 0.20

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