title: Histamine stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase.
abstract: Oxidative stress has been implicated in the pathogenesis of bronchial asthma. Besides granulocytes, the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma-related oxidative stress. Histamine is a major inflammatory mediator present in large quantities in asthmatic airways. Whether histamine triggers epithelium-derived oxidative stress is unknown. We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine. We found that air-liquid interface cultures of primary human bronchial epithelial cells (BECs) and an immortalized BEC model (Cdk4/hTERT HBEC) produce H2O2 in response to histamine. The main source of airway epithelial H2O2 is an NADPH dual oxidase, Duox1. Out of the four histamine receptors (H1R-H4R), H1R has the highest expression in BECs and mediates the H2O2-producing effects of histamine. IL-4 induces Duox1 gene and protein expression levels and enhances histamine-induced H2O2 production by epithelial cells. Using HEK-293 cells expressing Duox1 or Duox2 and endogenous H1R, histamine triggers an immediate intracellular calcium signal and H2O2 release. Overexpression of H1R further increases the oxidative output of Duox-expressing HEK-293 cells. Our observations show that BECs respond to histamine with Duox-mediated H2O2 production. These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways, suggesting novel therapeutic targets for treating asthmatic airway disease.
authors: 1 Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia; and.
authors: Balázs
authors: B
authors: Rada
authors: Howard E
authors: HE
authors: Boudreau
authors: Jonathan J
authors: JJ
authors: Park
authors: Thomas L
authors: TL
authors: Leto
mesh_terms: D001980:Bronchi / Q000378:metabolism*; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000074623:Dual Oxidases; D004847:Epithelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
chemical_list: D016207:Cytokines; D011969:Receptors, Histamine H1; D015847:Interleukin-4; D006632:Histamine; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C509186:TERT protein, human; D019098:Telomerase
references: Am J Respir Cell Mol Biol. 2013 Mar;48(3):337-45
references: 23239498
references: FASEB J. 2009 Apr;23(4):1205-18
references: 19074510
references: FASEB J. 2003 Aug;17(11):1502-4
references: 12824283
references: Am J Respir Cell Mol Biol. 2000 Jun;22(6):665-71
references: 10837362
references: Int J Mol Med. 2006 Nov;18(5):925-31
references: 17016623
references: Am J Respir Crit Care Med. 2013 Jan 1;187(1):34-41
references: 23204253
references: Chest. 2001 Oct;120(4):1136-9
references: 11591550
references: Curr Med Chem. 2011;18(10):1432-43
references: 21428897
references: J Immunol. 2001 Nov 15;167(10):5948-54
references: 11698473
references: FEBS Lett. 2005 Aug 29;579(21):4911-7
references: 16111680
references: Mucosal Immunol. 2011 Mar;4(2):158-71
references: 20962773
references: J Biol Chem. 2009 Jun 26;284(26):17858-67
references: 19386603
references: J Biol Chem. 2004 Aug 27;279(35):36454-61
references: 15210697
references: J Biol Regul Homeost Agents. 2012 Jan-Mar;26(1 Suppl):S41-8
references: 22691249
references: J Biol Chem. 2005 Aug 26;280(34):30046-54
references: 15972824
references: J Allergy Clin Immunol. 2011 Dec;128(6):1153-62
references: 21824648
references: Am J Respir Cell Mol Biol. 2005 May;32(5):462-9
references: 15677770
references: Chest. 2002 Feb;121(2):338-46
references: 11834641
references: Clin Exp Allergy. 2009 Dec;39(12):1786-800
references: 20085595
references: J Clin Invest. 2006 Jun;116(6):1624-32
references: 16680192
references: J Biol Chem. 2007 Feb 2;282(5):3213-20
references: 17135261
references: Trends Microbiol. 2013 Feb;21(2):73-81
references: 23140890
references: Am J Respir Crit Care Med. 2007 Jan 15;175(2):174-83
references: 17082494
references: Am J Respir Cell Mol Biol. 2012 Sep;47(3):261-70
references: 22538865
references: J Immunol. 2007 Apr 15;178(8):5144-53
references: 17404297
references: Pharmacology. 2007;80(4):219-26
references: 17622767
references: J Biol Chem. 2000 Jul 28;275(30):23227-33
references: 10806195
references: J Biol Chem. 1999 Dec 24;274(52):37265-9
references: 10601291
references: Am J Respir Crit Care Med. 1994 Feb;149(2 Pt 1):519-25
references: 8306055
references: Am J Respir Cell Mol Biol. 1996 Jan;14(1):104-12
references: 8534481
references: J Immunol. 2000 Feb 1;164(3):1546-52
references: 10640773
references: Proc Natl Acad Sci U S A. 1988 Aug;85(16):5951-5
references: 2457904
references: Curr Opin Pharmacol. 2004 Jun;4(3):241-50
references: 15140415
references: Eur Respir J. 1997 Mar;10(3):519-21
references: 9072978
references: Biochim Biophys Acta. 2011 Nov;1810(11):1035-44
references: 21397663
references: Mol Pharmacol. 2001 Nov;60(5):1133-42
references: 11641442
references: Cancer Res. 2004 Dec 15;64(24):9027-34
references: 15604268
references: Cancer Res. 2008 Feb 15;68(4):1037-45
references: 18281478
references: Toxicol Sci. 2002 Jun;67(2):275-83
references: 12011487
references: Free Radic Biol Med. 2013 Dec;65:38-46
references: 23770197
references: FEBS Lett. 2010 Mar 5;584(5):917-22
references: 20085766
references: J Allergy Clin Immunol. 1986 Aug;78(2):321-8
references: 2426322
references: Am J Respir Crit Care Med. 1998 Oct;158(4):1042-6
references: 9769258
references: Biochem Pharmacol. 2005 Feb 1;69(3):433-49
references: 15652235
references: J Immunol. 2008 Oct 1;181(7):4883-93
references: 18802092
references: FASEB J. 2012 Apr;26(4):1704-16
references: 22247333
references: Acta Otolaryngol. 2012 Jun;132 Suppl 1:S37-43
references: 22582780
references: Pediatr Pulmonol Suppl. 1999;18:54-5
references: 10093095
references: J Allergy Clin Immunol. 2012 Oct;130(4):829-42; quiz 843-4
references: 22951057
references: Circ Shock. 1991 Nov;35(3):174-80
references: 1723354
references: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):767-72
references: 15640347
references: Differentiation. 2006 Apr;74(4):141-8
references: 16683984