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Direct Inhibitory Effect of the PDE4 Inhibitor Roflumilast on Neutrophil Migration in Chronic Obstructive Pulmonary Disease.
Am J Respir Cell Mol Biol. 2019 04; 60(4):445-453.AJ

Abstract

Neutrophilic inflammation is characteristic of chronic obstructive pulmonary disease (COPD); yet, there are no effective antiinflammatory therapies. The PDE4 inhibitor roflumilast is approved for use in COPD and suppresses sputum neutrophilia. The mechanism underlying this observation is unclear; therefore, this study addressed whether roflumilast directly affected neutrophil migration. Blood-derived neutrophils were isolated from nonsmokers, smokers, and patients with COPD, and chemotaxis was measured using Boyden chambers. Intracellular calcium ion concentration was measured by fluorimetry, and shape change and CD11b expression were measured by flow cytometry. Neutrophils from patients with COPD showed enhanced chemotactic responses toward both CXCL1 and leukotriene B4 compared with control cells. Chemotaxis was inhibited by both the active metabolite roflumilast N-oxide and rolipram in a concentration-dependent manner with no difference in responsiveness between subjects. Roflumilast N-oxide and rolipram were less efficacious against CXCL1 and leukotriene B4-mediated intracellular calcium ion concentration, suggesting that inhibition was not via this pathway. Both PDE4 inhibitors attenuated chemoattractant-mediated shape change and CD11b upregulation, suggesting common mechanisms. The stable cAMP analog 8-bromoadenosine 3',5'-cAMP inhibited chemotaxis, as did the direct Epac1 (exchange protein directly activated by cAMP 1) activator 8-(4-chlorophenylthio)-2'-O-methyladenosine 3',5'-cAMP but not the direct protein kinase A activator N6-benzoyladenosine-3',5'-cAMP. These data suggest that roflumilast inhibits neutrophil chemotaxis directly via a cAMP-mediated mechanism requiring activation of Epac1 and that Epac1 activators could reduce COPD neutrophilic inflammation.

Authors+Show Affiliations

Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30395484

Citation

Dunne, Amy E., et al. "Direct Inhibitory Effect of the PDE4 Inhibitor Roflumilast On Neutrophil Migration in Chronic Obstructive Pulmonary Disease." American Journal of Respiratory Cell and Molecular Biology, vol. 60, no. 4, 2019, pp. 445-453.
Dunne AE, Kawamatawong T, Fenwick PS, et al. Direct Inhibitory Effect of the PDE4 Inhibitor Roflumilast on Neutrophil Migration in Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol. 2019;60(4):445-453.
Dunne, A. E., Kawamatawong, T., Fenwick, P. S., Davies, C. M., Tullett, H., Barnes, P. J., & Donnelly, L. E. (2019). Direct Inhibitory Effect of the PDE4 Inhibitor Roflumilast on Neutrophil Migration in Chronic Obstructive Pulmonary Disease. American Journal of Respiratory Cell and Molecular Biology, 60(4), 445-453. https://doi.org/10.1165/rcmb.2018-0065OC
Dunne AE, et al. Direct Inhibitory Effect of the PDE4 Inhibitor Roflumilast On Neutrophil Migration in Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol. 2019;60(4):445-453. PubMed PMID: 30395484.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Direct Inhibitory Effect of the PDE4 Inhibitor Roflumilast on Neutrophil Migration in Chronic Obstructive Pulmonary Disease. AU - Dunne,Amy E, AU - Kawamatawong,Theerasuk, AU - Fenwick,Peter S, AU - Davies,Ceri M, AU - Tullett,Hannah, AU - Barnes,Peter J, AU - Donnelly,Louise E, PY - 2018/11/6/pubmed PY - 2019/12/19/medline PY - 2018/11/6/entrez KW - PDE4 KW - chemotaxis KW - neutrophil SP - 445 EP - 453 JF - American journal of respiratory cell and molecular biology JO - Am J Respir Cell Mol Biol VL - 60 IS - 4 N2 - Neutrophilic inflammation is characteristic of chronic obstructive pulmonary disease (COPD); yet, there are no effective antiinflammatory therapies. The PDE4 inhibitor roflumilast is approved for use in COPD and suppresses sputum neutrophilia. The mechanism underlying this observation is unclear; therefore, this study addressed whether roflumilast directly affected neutrophil migration. Blood-derived neutrophils were isolated from nonsmokers, smokers, and patients with COPD, and chemotaxis was measured using Boyden chambers. Intracellular calcium ion concentration was measured by fluorimetry, and shape change and CD11b expression were measured by flow cytometry. Neutrophils from patients with COPD showed enhanced chemotactic responses toward both CXCL1 and leukotriene B4 compared with control cells. Chemotaxis was inhibited by both the active metabolite roflumilast N-oxide and rolipram in a concentration-dependent manner with no difference in responsiveness between subjects. Roflumilast N-oxide and rolipram were less efficacious against CXCL1 and leukotriene B4-mediated intracellular calcium ion concentration, suggesting that inhibition was not via this pathway. Both PDE4 inhibitors attenuated chemoattractant-mediated shape change and CD11b upregulation, suggesting common mechanisms. The stable cAMP analog 8-bromoadenosine 3',5'-cAMP inhibited chemotaxis, as did the direct Epac1 (exchange protein directly activated by cAMP 1) activator 8-(4-chlorophenylthio)-2'-O-methyladenosine 3',5'-cAMP but not the direct protein kinase A activator N6-benzoyladenosine-3',5'-cAMP. These data suggest that roflumilast inhibits neutrophil chemotaxis directly via a cAMP-mediated mechanism requiring activation of Epac1 and that Epac1 activators could reduce COPD neutrophilic inflammation. SN - 1535-4989 UR - https://www.unboundmedicine.com/medline/citation/30395484/Direct_Inhibitory_Effect_of_the_PDE4_Inhibitor_Roflumilast_on_Neutrophil_Migration_in_Chronic_Obstructive_Pulmonary_Disease_ L2 - https://www.atsjournals.org/doi/10.1165/rcmb.2018-0065OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -