Doxofylline does not increase formoterol-induced cAMP nor MKP-1 expression in ASM cells resulting in lack of anti-inflammatory effect

Patel, BS; Kugel, MJ; Baehring, G; Ammit, AJ

Doxofylline does not increase formoterol-induced cAMP nor MKP-1 expression in ASM cells resulting in lack of anti-inflammatory effect

Patel, BS Kugel, MJ Baehring, G Ammit, AJ

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Publication Type:: Journal Article
Citation:: Pulmonary Pharmacology and Therapeutics, 2017, 45 pp. 34 - 39
Issue Date:: 2017-08-01

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Field	Value	Language
dc.contributor.author	Patel, BS	en_US
dc.contributor.author	Kugel, MJ	en_US
dc.contributor.author	Baehring, G	en_US
dc.contributor.author	Ammit, AJ https://orcid.org/0000-0003-0555-2544	en_US
dc.date.available	2017-04-12	en_US
dc.date.issued	2017-08-01	en_US
dc.identifier.citation	Pulmonary Pharmacology and Therapeutics, 2017, 45 pp. 34 - 39	en_US
dc.identifier.issn	1094-5539	en_US
dc.identifier.uri	http://hdl.handle.net/10453/124266
dc.description.abstract	© 2017 The xanthine doxofylline has been examined in clinical trials and shown to have efficacy and greater tolerability than theophylline in asthma and chronic obstructive pulmonary disease. The ‘novofylline’ doxofylline has demonstrated bronchodilatory and anti-inflammatory actions in in vivo and ex vivo experimental models of respiratory disease. However, there are limited studies in vitro. We address this herein and examine whether doxofylline has anti-inflammatory impact on primary cultures of airway smooth muscle (ASM) cells. We conduct a series of investigations comparing and contrasting doxofylline with the archetypal xanthine, theophylline, and the specific phosphodiesterase (PDE) 4 inhibitor, cilomilast. We confirm that the xanthine drugs do not have action as PDE inhibitors in ASM cells. Unlike cilomilast, doxofylline (and theophylline) do not increase cAMP production in ASM cells induced by long-acting β2-agonist formoterol. Similar to theophylline, and consistent with the lack of cAMP potentiation, doxofylline does not augment formoterol-induced upregulation of the anti-inflammatory protein mitogen-activated protein kinase phosphatase 1 (MKP-1). However, when we examine the effect of doxofylline on secretion of the interleukin 8 from ASM cells stimulated by tumour necrosis factor (an in vitro surrogate measure of inflammation), there was no repression of inflammation. This is in contrast to the anti-inflammatory impact exerted by theophylline and cilomilast in confirmatory experiments. In summary, our study is the first to examine the effect of doxofylline on ASM cells in vitro and highlights some distinct differences between two key members of xanthine drug family, doxofylline and theophylline.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/
dc.relation.ispartof	Pulmonary Pharmacology and Therapeutics	en_US
dc.relation.isbasedon	10.1016/j.pupt.2017.04.006	en_US
dc.subject.classification	Respiratory System	en_US
dc.subject.mesh	Bronchi	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Myocytes, Smooth Muscle	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Inflammation	en_US
dc.subject.mesh	Cyclohexanecarboxylic Acids	en_US
dc.subject.mesh	Nitriles	en_US
dc.subject.mesh	Theophylline	en_US
dc.subject.mesh	Tumor Necrosis Factor-alpha	en_US
dc.subject.mesh	Cyclic AMP	en_US
dc.subject.mesh	Bronchodilator Agents	en_US
dc.subject.mesh	Anti-Inflammatory Agents	en_US
dc.subject.mesh	Interleukin-8	en_US
dc.subject.mesh	Phosphodiesterase Inhibitors	en_US
dc.subject.mesh	Dual Specificity Phosphatase 1	en_US
dc.subject.mesh	Formoterol Fumarate	en_US
dc.title	Doxofylline does not increase formoterol-induced cAMP nor MKP-1 expression in ASM cells resulting in lack of anti-inflammatory effect	en_US
dc.type	Journal Article
utslib.citation.volume	45	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.publication-status	Published	en_US
pubs.volume	45	en_US

Abstract:

© 2017 The xanthine doxofylline has been examined in clinical trials and shown to have efficacy and greater tolerability than theophylline in asthma and chronic obstructive pulmonary disease. The ‘novofylline’ doxofylline has demonstrated bronchodilatory and anti-inflammatory actions in in vivo and ex vivo experimental models of respiratory disease. However, there are limited studies in vitro. We address this herein and examine whether doxofylline has anti-inflammatory impact on primary cultures of airway smooth muscle (ASM) cells. We conduct a series of investigations comparing and contrasting doxofylline with the archetypal xanthine, theophylline, and the specific phosphodiesterase (PDE) 4 inhibitor, cilomilast. We confirm that the xanthine drugs do not have action as PDE inhibitors in ASM cells. Unlike cilomilast, doxofylline (and theophylline) do not increase cAMP production in ASM cells induced by long-acting β2-agonist formoterol. Similar to theophylline, and consistent with the lack of cAMP potentiation, doxofylline does not augment formoterol-induced upregulation of the anti-inflammatory protein mitogen-activated protein kinase phosphatase 1 (MKP-1). However, when we examine the effect of doxofylline on secretion of the interleukin 8 from ASM cells stimulated by tumour necrosis factor (an in vitro surrogate measure of inflammation), there was no repression of inflammation. This is in contrast to the anti-inflammatory impact exerted by theophylline and cilomilast in confirmatory experiments. In summary, our study is the first to examine the effect of doxofylline on ASM cells in vitro and highlights some distinct differences between two key members of xanthine drug family, doxofylline and theophylline.

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http://hdl.handle.net/10453/124266