Figures
- FIGURE 1
Role of pan-phosphodiesterase 4 (PDE4)/PDE4B in homeostasis and disease. AIP: aromatic hydrocarbon receptor-interacting protein; β-AR: β2 adrenergic receptor; GH: growth hormone; PKA: protein kinase A; SNP: single nucleotide polymorphism; Th2: T-helper 2 cell; TSHR: thyroid-stimulating hormone receptor.
- FIGURE 2
Hypothesised role of pan-phosphodiesterase 4 (PDE4)/PDE4B inhibition in treating lung fibrosis. Dotted lines indicated hypothesised role of PDE4B preferential inhibition on inflammatory and fibrotic pathways. ECM: extracellular matrix; EPAC1/2: exchange protein directly activated by cAMP 1/2; GPCR: G protein-coupled receptor; PKA: protein kinase A.
Tables
- TABLE 1
The phosphodiesterase (PDE) superfamily
PDE family Localisation Substrate specificity Main functions References PDE1 Widely distributed; adipose, brain, kidney, heart, skeletal muscle, testes and thyroid cAMP
cGMPVascular smooth muscle contraction, sperm function, dopaminergic signalling, immune cell activation [76–81] PDE2 Widely distributed; significant in the brain, heart (myocytes), liver, adrenal cortex, endothelium and platelets cAMP
cGMPRegulates aldosterone secretion, phosphorylation of calcium channels in heart, cGMP in neurons; endothelial cell function under inflammatory conditions [79, 82–84] PDE3 Widely distributed; significant in cardiac and vascular myocytes, brain, liver, adipose tissues, pancreatic β-cells, endothelium, epithelium, oocytes and platelets cAMP
cGMPCardiac contractility, platelet aggregation, vascular smooth muscle contraction, oocyte maturation, renin release, insulin signalling, cell cycle/proliferation [85–90] PDE4 Widely distributed; significant in cells of the cardiovascular, neural, immune and inflammatory systems cAMP Brain function, monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, fertility, vasodilation, cardiac contractility [90–93] PDE5 Widely distributed; significant in vascular myocytes, diseased cardiac myocytes, lung, brain, platelets, kidney, gastrointestinal tissues and penis cGMP Vascular smooth muscle contraction, platelet aggregation, cGMP signalling in brain [94–97] PDE6 Expression limited to photoreceptors and pineal gland cGMP Phototransduction [98, 99] PDE7 Widely distributed, including brain, heart, liver kidney, placenta and lymphoid tissues cAMP Immune cell activation, memory [100–102] PDE8 Widely distributed, with high expression in adipose tissue, brain, kidney, testes and thyroid cAMP T-cell activation, sperm or Leydig cell function, T4 and T3 production [103–105] PDE9 Brain, heart, adipose tissue and liver cGMP NO-cGMP signalling in brain [106–108] PDE10 Expression limited to brain and testes cAMP
cGMPLearning and memory [79, 109–111] PDE11 Expression predominantly in prostate, testes and skeletal muscle cAMP
cGMPSperm development and function [111, 112] cGMP: cyclic guanosine monophosphate; NO: nitric oxide.
- TABLE 2
The phosphodiesterase 4 (PDE4) subfamily
PDE4 subtype Organ systems Variant localisation# Knockout phenotype References A (A1–11) Ubiquitous, with variant-specific tissue distribution; high levels in adipose tissue, brain, heart and testes • PDE4A4B: T-cells, monocytes, neutrophils
• PDE4A7: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, neutrophils
• PDE4A10: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, neutrophils, heart and small intestine; present in adult brain but not fetal brain
• PDE4A11: various tissues, with high expression in fetal, but not adult, brain• Increased anxiogenic-like behaviour
• Increased emotional memory[20, 22, 113–115] B (B1–5) Widely distributed, with variant-specific tissue distribution; high levels in brain, lung, immune cells, heart and skeletal muscle • PDE4B1: bronchoalveolar macrophages, peripheral blood monocytes, T-cells
• PDE4B2: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, leukocytes, especially neutrophils; major PDE4B subtype in normal B-cells, abundant in naïve and memory B-cells, low in centroblasts and centrocytes• No airway inflammation or acute airway hyperactivity in response to allergen challenge
• Inhibited TGF-β-induced differentiation into myofibroblasts
• Inhibited injury-induced neutrophil recruitment
• Reduced inflammatory response to LPA in monocytes and macrophages
• Inhibition of TNF-α production
• Decreased striatal dopamine and 5-HT activity, associated with reduced pre-pulse inhibition and baseline motor activity
• Increased anxiogenic-like behaviour[22, 29, 116–123] C (1–5) Testes and other tissues; low in lung, absent in blood and immune cells • PDE4C-Δ54: testes-specific
• PDE4C1–3: identified in human tissue, although there are limited data on expression of PDE4C variants• None published [20, 21, 124] D (D1–9) Brain, skeletal muscle and immune cells • PDE4D1: bronchoalveolar macrophages, peripheral blood monocytes, T-cells, neutrophils
• PDE4D2: bronchoalveolar macrophages, peripheral blood monocytes, T-cells
• PDE4D3: bronchoalveolar macrophages, peripheral blood monocytes, T-cells
• PDE4D4: brain-specific
• PDE4D6: brain-specific
• PDE4D7: ubiquitous, with high levels in lung and kidney
• PDE4D8: heart and skeletal muscle, indicating muscle-specific expression
• PDE4D5: dominant in well-differentiated human bronchial epithelium cells• Inhibited injury-induced neutrophil recruitment
• Impaired airway contractile responses induced by cholinergic stimulation, and little or no airway hyper-reactivity induced by exposure to allergen
• Delayed growth, impaired ovulation, reduced postnatal viability and refractory to muscarinic cholinergic stimulation
• Loss of β2-, but not β1-, adrenergic receptor-regulated responses in cardiac cells
• Growth inhibition and apoptotic cell death in malignant cells, but not in nonmalignant cells
• Anti-depressive behaviour and reduced antidepressant responses to rolipram
• Enhanced performance in memory tasks, and increased hippocampal neurogenesis and phosphorylated CREB
• Increased emesis[33, 40, 117, 125–130] #: variant localisation based on data from human tissue samples and human PDE4-subtype gene expression in vitro. 5-HT: 5-hydroxytryptamine; CREB: cyclic adenosine monophosphate response element-binding protein; LPA: lysophosphatidic acid; PDE: phosphodiesterase; TGF-β: transforming growth factor-β; TNF-α: tumour necrosis factor-α.
Vol 32 Issue 167
Table of Contents
Phosphodiesterase 4B inhibition: a potential novel strategy for treating pulmonary fibrosis
