Inhibition of phosphodiesterase 4 modulates cytokine induction from toll like receptor activated, but not rhinovirus infected, primary human airway smooth muscle

Virus-induced exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are a significant health burden and occur even in those receiving the best current therapies. Rhinovirus (RV) infections are responsible for half of all COPD exacerbations. The mechanism by which exacerbations occur remains...

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Published in:	Respiratory research Vol. 14; no. 1; p. 127
Main Authors:	Van Ly, David, De Pedro, Monique, James, Peter, Morgan, Lucy, Black, Judith L, Burgess, Janette K, Oliver, Brian G G
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 15-11-2013 BioMed Central
Subjects:	Adolescent Adult Aged Aminoquinolines - pharmacology Asthma Australia Benzamides - pharmacology Bronchi - metabolism Bronchi - pathology Bronchi - virology Care and treatment Cell culture Cells, Cultured Chronic obstructive pulmonary disease Colleges & universities Comorbidity Councils Cyclic adenylic acid Cyclic Nucleotide Phosphodiesterases, Type 4 - drug effects Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism Cytokines Cytokines - metabolism Development and progression Diseases Enzyme-linked immunosorbent assay Epithelial Cells - metabolism Epithelial Cells - pathology Epithelial Cells - virology Experiments Female Hospitals Humans Immune system In Vitro Techniques Inhibitors Lungs Male Middle Aged Mortality Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Myocytes, Smooth Muscle - virology Phosphodiesterase 4 Inhibitors - pharmacology Physiological aspects Picornaviridae Infections - epidemiology Picornaviridae Infections - metabolism Picornavirus infections Poly I-C - pharmacology Proteins Pulmonary Disease, Chronic Obstructive - epidemiology Pulmonary Disease, Chronic Obstructive - metabolism Pulmonary Disease, Chronic Obstructive - virology Pyridines - pharmacology Rhinovirus Risk factors Scholarships & fellowships Smooth muscle Toll-Like Receptor 3 - agonists Toll-Like Receptor 3 - drug effects Toll-Like Receptor 7 - agonists Toll-Like Receptor 7 - drug effects Toll-Like Receptor 8 - agonists Toll-Like Receptor 8 - drug effects Toll-Like Receptors - drug effects Toll-Like Receptors - metabolism Viral infections Young Adult Australia New South Wales Australia
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Summary:	Virus-induced exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are a significant health burden and occur even in those receiving the best current therapies. Rhinovirus (RV) infections are responsible for half of all COPD exacerbations. The mechanism by which exacerbations occur remains undefined, however it is likely to be due to virus-induced inflammation. Given that phophodiesterase 4 (PDE4) inhibitors have an anti-inflammatory effect in patients with COPD they present a potential therapy prior to, and during, these exacerbations. In the present study we investigated whether the PDE4 inhibitor piclamilast (10(-6) M) could alter RV or viral mimetic (5 μg/mL of imiquimod or poly I:C) induced inflammation and RV replication in primary human airway smooth muscle cells (ASMC) and bronchial epithelial cells (HBEC). The mediators IL-6, IL-8, prostaglandin E2 and cAMP production were assayed by ELISA and RV replication was assayed by viral titration. We found that in ASMCs the TLR3 agonist poly I:C induced IL-8 release was reduced while induced IL-6 release by the TLR7/8 agonist imiquimod was further increased by the presence of piclamilast. However, in RV infected ASMCs, virus replication and induced mediator release were unaltered by piclamilast, as was also found in HBECs. The novel findings of this study reveal that although PDE inhibitors may not influence RV-induced cytokine production in ASMCs and replication in either ASMCs or HBECs, they have the capacity to be anti-inflammatory during TLR activation by modulating the induction of these chemotactic cytokines. By extrapolating our in vitro findings to exacerbations of COPD in vivo this suggests that PDE4 inhibitors may have beneficial anti-inflammatory properties when patients are infected with bacteria or viruses other than RV.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1465-9921 1465-993X 1465-993X 1465-9921
DOI:	10.1186/1465-9921-14-127