title: Role of cyclooxygenase-2 in exacerbation of allergen-induced airway remodeling by multiwalled carbon nanotubes.
abstract: The emergence of nanotechnology has produced a multitude of engineered nanomaterials such as carbon nanotubes (CNTs), and concerns have been raised about their effects on human health, especially for susceptible populations such as individuals with asthma. Multiwalled CNTs (MWCNTs) have been shown to exacerbate ovalbumin (OVA)-induced airway remodeling in mice. Moreover, cyclooxygenase-2 (COX-2) has been described as a protective factor in asthma. We postulated that COX-2-deficient (COX-2(-/-)) mice would be susceptible to MWCNT-induced exacerbations of allergen-induced airway remodeling, including airway inflammation, fibrosis, and mucus-cell metaplasia (i.e., the formation of goblet cells). Wild-type (WT) or COX-2(-/-) mice were sensitized to OVA to induce allergic airway inflammation before a single dose of MWCNTs (4 mg/kg) delivered to the lungs by oropharyngeal aspiration. MWCNTs significantly increased OVA-induced lung inflammation and mucus-cell metaplasia in COX-2(-/-) mice compared with WT mice. However, airway fibrosis after exposure to allergen and MWCNTs was no different between WT and COX-2(-/-) mice. Concentrations of certain prostanoids (prostaglandin D2 and thromboxane B2) were enhanced by OVA or MWCNTs in COX-2(-/-) mice. No differences in COX-1 mRNA concentrations were evident between WT and COX-2(-/-) mice treated with OVA and MWCNTs. Interestingly, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13 and IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2(-/-) mice, but not in WT mice. We conclude that exacerbations of allergen-induced airway inflammation and mucus-cell metaplasia by MWCNTs are enhanced by deficiencies in COX-2, and are associated with the activation of a mixed Th1/Th2/Th17 immune response.
authors: 1 Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina.
authors: Brian C
authors: BC
authors: Sayers
authors: Alexia J
authors: AJ
authors: Taylor
authors: Ellen E
authors: EE
authors: Glista-Baker
authors: Jeanette K
authors: JK
authors: Shipley-Phillips
authors: Ryan T
authors: RT
authors: Dackor
authors: Matthew L
authors: ML
authors: Edin
authors: Fred B
authors: FB
authors: Lih
authors: Kenneth B
authors: KB
authors: Tomer
authors: Darryl C
authors: DC
authors: Zeldin
authors: Robert
authors: R
authors: Langenbach
authors: James C
authors: JC
authors: Bonner
mesh_terms: D056151:Airway Remodeling / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000485:Allergens / Q000276:immunology*; D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008679:Metaplasia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000276:immunology / Q000378:metabolism; D037742:Nanotubes, Carbon; D010047:Ovalbumin / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D016207:Cytokines; D008565:Membrane Proteins; D037742:Nanotubes, Carbon; D010047:Ovalbumin; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse
references: J Clin Invest. 2005 Mar;115(3):747-54
references: 15711639
references: Am J Respir Cell Mol Biol. 2009 Mar;40(3):349-58
references: 18787175
references: Prostaglandins Other Lipid Mediat. 2009 Apr;88(3-4):111-6
references: 19114118
references: J Allergy Clin Immunol. 2001 Apr;107(4):664-70
references: 11295656
references: Nat Rev Drug Discov. 2007 Apr;6(4):313-25
references: 17396136
references: Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):676-81
references: 10934105
references: Nat Nanotechnol. 2009 Nov;4(11):747-51
references: 19893520
references: J Immunol. 2009 Jun 15;182(12):7818-27
references: 19494306
references: Am J Respir Crit Care Med. 2002 Apr 15;165(8):1154-60
references: 11956061
references: Am J Physiol Lung Cell Mol Physiol. 2003 Sep;285(3):L755-61
references: 12794002
references: Proc Am Thorac Soc. 2007 Jul;4(3):217-20
references: 17607002
references: Nat Immunol. 2010 Oct;11(10):928-35
references: 20802484
references: Am J Respir Crit Care Med. 1997 Apr;155(4):1376-83
references: 9105082
references: Eur J Pharmacol. 2010 Jul 25;638(1-3):142-9
references: 20447387
references: Proc Am Thorac Soc. 2010 May;7(2):138-41
references: 20427587
references: J Allergy Clin Immunol. 2006 Jun;117(6):1446-54
references: 16751012
references: Science. 1998 Dec 18;282(5397):2258-61
references: 9856949
references: Clin Immunol. 2006 Nov;121(2):227-35
references: 16979384
references: Clin Exp Allergy. 2008 May;38(5):774-80
references: 18341619
references: Nat Med. 2002 Aug;8(8):885-9
references: 12091879
references: J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138
references: 17983880
references: Am J Physiol Lung Cell Mol Physiol. 2011 Nov;301(5):L636-44
references: 21873451
references: Am J Respir Crit Care Med. 2011 Jul 1;184(1):37-49
references: 21474648
references: J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S95-102
references: 20176271
references: Int Arch Allergy Immunol. 2001 Jan-Mar;124(1-3):109-12
references: 11306943
references: Pharmacotherapy. 1997 Jan-Feb;17(1 Pt 2):3S-12S
references: 9017783
references: Part Fibre Toxicol. 2012 May 09;9:14
references: 22571318
references: Am J Physiol Lung Cell Mol Physiol. 2008 Sep;295(3):L400-11
references: 18641236
references: J Immunol. 2008 Jan 1;180(1):541-9
references: 18097056
references: Nat Rev Immunol. 2008 Mar;8(3):169-82
references: 18301422
references: Am J Respir Cell Mol Biol. 2007 Sep;37(3):300-8
references: 17496151
references: J Allergy Clin Immunol. 2011 Sep;128(3):451-62; quiz 463-4
references: 21636119
references: J Allergy Clin Immunol. 2007 Sep;120(3):586-93
references: 17628646
references: J Allergy Clin Immunol. 2006 Feb;117(2):269-74
references: 16461126
references: Environ Health Perspect. 2005 Jul;113(7):823-39
references: 16002369
references: Am J Respir Crit Care Med. 2003 Jun 1;167(11):1509-15
references: 12626351
references: Part Fibre Toxicol. 2011 Aug 18;8:24
references: 21851604
references: J Allergy Clin Immunol. 2002 Jun;109(6):980-7
references: 12063528
references: J Clin Invest. 1999 Sep;104(6):721-32
references: 10491407
references: Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L797-805
references: 16603593
references: Am J Respir Crit Care Med. 1999 Oct;160(4):1150-6
references: 10508801
references: J Allergy Clin Immunol. 2003 Feb;111(2):215-25; quiz 226
references: 12589337
references: Curr Allergy Asthma Rep. 2011 Oct;11(5):388-94
references: 21773747
references: J Lipid Res. 2002 Sep;43(9):1563-78
references: 12235189
references: J Exp Med. 2001 Sep 17;194(6):809-21
references: 11560996
references: Toxicol Appl Pharmacol. 2009 Jun 15;237(3):306-16
references: 19371758
references: Respirology. 2005 Mar;10(2):149-56
references: 15823178
references: Science. 2000 Mar 17;287(5460):2013-7
references: 10720327
references: J Physiol Pharmacol. 2007 Jun;58(2):207-18
references: 17622692
references: J Allergy Clin Immunol. 2012 Oct;130(4):829-42; quiz 843-4
references: 22951057
references: J Exp Med. 1998 Feb 16;187(4):517-23
references: 9463402