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

Respiratory Research

Brian GG Oliver²  Janette K Burgess²  Judith L Black²  Lucy Morgan¹  Peter James²  Monique De Pedro²  David Van Ly² 

[1] Department of Thoracic Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia;Respiratory Research Group, Discipline of Pharmacology, The University of Sydney, Sydney, New South Wales, Australia

关键词: Airway smooth muscle;    COPD;    Phosphodiesterase 4;    Imiquimod;    Formoterol;    Poly I: C;    Rhinovirus;    Piclamilast;   

Others  :  792319
DOI  :  10.1186/1465-9921-14-127

 received in 2013-08-08, accepted in 2013-11-11,  发布年份 2013

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusion

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.

【 授权许可】

   
2013 Van Ly et al.; licensee BioMed Central Ltd.

【 图 表 】

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