title: The beta-2-adrenoreceptor agonists, formoterol and indacaterol, but not salbutamol, effectively suppress the reactivity of human neutrophils in vitro.
abstract: The clinical relevance of the anti-inflammatory properties of beta-2 agonists remains contentious possibly due to differences in their molecular structures and agonist activities. The current study has compared the effects of 3 different categories of β 2-agonists, namely, salbutamol (short-acting), formoterol (long-acting) and indacaterol (ultra-long-acting), at concentrations of 1-1000 nM, with human blood neutrophils in vitro. Neutrophils were activated with either N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP, 1 µM) or platelet-activating factor (PAF, 200 nM) in the absence and presence of the β 2-agonists followed by measurement of the generation of reactive oxygen species and leukotriene B4, release of elastase, and expression of the β 2-integrin, CR3, using a combination of chemiluminescence, ELISA, colorimetric, and flow cytometric procedures respectively. These were correlated with alterations in the concentrations of intracellular cyclic-AMP and cytosolic Ca(2+). At the concentrations tested, formoterol and indacaterol caused equivalent, significant (P < 0.05 at 1-10 nM) dose-related inhibition of all of the pro-inflammatory activities tested, while salbutamol was much less effective (P < 0.05 at 100 nM and higher). Suppression of neutrophil reactivity was accompanied by elevations in intracellular cAMP and accelerated clearance of Ca(2+) from the cytosol of activated neutrophils. These findings demonstrate that β 2-agonists vary with respect to their suppressive effects on activated neutrophils.
authors.affiliation: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa.
authors.forename: Ronald
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa ; Tshwane Academic Division of the National Health Laboratory Service, Pretoria 0001, South Africa.
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Theron
authors.affiliation: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Steel
authors.affiliation: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa.
authors.forename: Chrisna
authors.initials: C
authors.lastname: Durandt
authors.affiliation: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Tintinger
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg 2193, South Africa.
authors.forename: Charles
authors.initials: C
authors.lastname: Feldman
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D005434:Flow Cytometry; D000068759:Formoterol Fumarate; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D010101:Oxygen Consumption; D010196:Pancreatic Elastase / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D015363:Quinolones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D004983:Ethanolamines; D007189:Indans; D015363:Quinolones; D017382:Reactive Oxygen Species; D007975:Leukotriene B4; C510790:indacaterol; D000242:Cyclic AMP; D010196:Pancreatic Elastase; D000420:Albuterol; D002118:Calcium; D000068759:Formoterol Fumarate
references.citation: Br J Pharmacol. 2009 Sep;158(1):267-76
references.pmid: 19371332
references.citation: Eur J Clin Pharmacol. 2009 Sep;65(9):853-71
references.pmid: 19557399
references.citation: Am J Respir Crit Care Med. 2011 Sep 1;184(5):561-8
references.pmid: 21562125
references.citation: Respir Res. 2012 Mar 27;13:28
references.pmid: 22452977
references.citation: Int J Chron Obstruct Pulmon Dis. 2013;8:425-32
references.pmid: 24082783
references.citation: Pharmacotherapy. 2012 May;32(5):456-74
references.pmid: 22499359
references.citation: J Biol Chem. 1985 Mar 25;260(6):3440-50
references.pmid: 3838314
references.citation: Biochem Pharmacol. 2012 Sep 1;84(5):581-90
references.pmid: 22587816
references.citation: BMC Pulm Med. 2011 May 26;11:31
references.pmid: 21615886
references.citation: COPD. 2013 Mar;10 Suppl 1:60-3
references.pmid: 23527919
references.citation: Br J Pharmacol. 2002 May;136(1):81-9
references.pmid: 11976271
references.citation: Drug Des Devel Ther. 2013 Nov 22;7:1387-98
references.pmid: 24285920
references.citation: Eur Cytokine Netw. 2010 Sep;21(3):177-85
references.pmid: 20724237
references.citation: Eur Respir J. 2010 Dec;36(6):1417-24
references.pmid: 20413544
references.citation: Am J Respir Cell Mol Biol. 2006 Oct;35(4):407-14
references.pmid: 16690986
references.citation: Br J Pharmacol. 2004 Dec;143(8):1033-41
references.pmid: 15477226
references.citation: Br J Pharmacol. 1998 Jun;124(3):547-55
references.pmid: 9647480
references.citation: Int J Chron Obstruct Pulmon Dis. 2013;8:353-63
references.pmid: 23922496
references.citation: Lancet. 2012 Jan 21;379(9812):229-35
references.pmid: 22166903
references.citation: Chest. 2009 Oct;136(4):1095-1100
references.pmid: 19809050
references.citation: FASEB J. 2012 May;26(5):2137-44
references.pmid: 22318967
references.citation: J Allergy Clin Immunol. 1999 Aug;104(2 Pt 2):S10-7
references.pmid: 10452784
references.citation: Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32
references.pmid: 18323530
references.citation: PLoS One. 2013 May 31;8(5):e64556
references.pmid: 23741338
references.citation: J Allergy Clin Immunol. 2007 May;119(5):1055-62; quiz 1063-4
references.pmid: 17353033
references.citation: Curr Opin Pulm Med. 2006 Jan;12(1):7-11
references.pmid: 16357572
references.citation: Eur Respir J. 2009 Sep;34(3):757-69
references.pmid: 19720811
references.citation: Thorax. 2013 Feb;68(2):195-8
references.pmid: 22858928
references.citation: Allergol Int. 2008 Dec;57(4):291-8
references.pmid: 18797182
references.citation: Eur Respir J. 2011 Sep;38(3):721-7
references.pmid: 21233269
references.citation: J Allergy Clin Immunol. 2002 Dec;110(6 Suppl):S282-90
references.pmid: 12464937
references.citation: BMC Pulm Med. 2013 Apr 25;13:26
references.pmid: 23617268
references.citation: Am J Respir Cell Mol Biol. 2013 May;48(5):531-9
references.pmid: 23328639
references.citation: Clin Exp Immunol. 1997 Oct;110(1):132-8
references.pmid: 9353160
references.citation: Am J Respir Crit Care Med. 2013 Apr 1;187(7):690-6
references.pmid: 23348973