title: Pulmonary chemoreflex responses are potentiated by tumor necrosis factor-alpha in mice.
abstract: Inhalation of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine, induces airway hyperresponsiveness, and the underlying mechanism is not fully understood. Hypersensitivity of vagal bronchopulmonary C-fiber afferents is known to contribute to the airway hyperresponsiveness during an airway inflammatory reaction. Because activation of these afferents can elicit pulmonary chemoreflexes, this study was designed to determine if a pretreatment with TNF-α induced airway inflammation and enhanced the pulmonary chemoreflex sensitivity in anesthetized mice; and if so, whether the effect was mediated through activation of either or both of the TNF receptors, p55 and p75. Our results showed that TNF-α instilled into the lung caused an increased sensitivity of pulmonary chemoreflex responses to various chemical stimulants of the vagal bronchopulmonary C-fiber afferents. The increased sensitivity was found 24 h later, persisted at 48 h, and then gradually declined after several days. The TNF-α-induced airway hypersensitivity was accompanied by airway inflammation as shown by a striking elevation of the levels of eosinophils and neutrophils, several potent bronchoactive inflammatory mediators, and proinflammatory cytokines in the bronchoalveolar lavage fluid. Furthermore, the increase in pulmonary chemoreflex response caused by TNF-α was partially abrogated in both p55-null and p75-null mice, but completely abolished in p55/p75-null mice. In conclusion, TNF-α pretreatment induced airway inflammation and a sustained elevation of pulmonary chemoreflex sensitivity, which was mediated through an activation of both types of TNF receptors.
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
authors.forename: Ruei-Lung
authors.initials: RL
authors.lastname: Lin
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Lin
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Geer
authors.forename: Richard
authors.initials: R
authors.lastname: Kryscio
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Lee
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002628:Chemoreceptor Cells / Q000276:immunology* / Q000528:radiation effects; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D012018:Reflex / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha
keywords: C-fibers; airway inflammation; airway reflex; asthma; transient receptor potential vanilloid type 1
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10150-5
references.pmid: 12097645
references.citation: Thorax. 1999 Sep;54(9):825-57
references.pmid: 10456976
references.citation: Clin Exp Immunol. 1993 Oct;94(1):105-10
references.pmid: 7691450
references.citation: J Neurochem. 1998 May;70(5):1876-86
references.pmid: 9572271
references.citation: Ann Allergy. 1994 Mar;72(3):272-8
references.pmid: 8129221
references.citation: Chest. 2010 Nov;138(5):1196-201
references.pmid: 21051395
references.citation: Proc Natl Acad Sci U S A. 1990 Apr;87(8):3127-31
references.pmid: 2158104
references.citation: Immunol Cell Biol. 2001 Apr;79(2):132-40
references.pmid: 11264706
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Oct;299(4):L483-92
references.pmid: 20639352
references.citation: Am Rev Respir Dis. 1992 Sep;146(3):768-74
references.pmid: 1519861
references.citation: Respir Physiol Neurobiol. 2009 May 30;167(1):26-35
references.pmid: 18586581
references.citation: Curr Opin Immunol. 2008 Oct;20(5):538-44
references.pmid: 18579363
references.citation: N Engl J Med. 2006 Feb 16;354(7):697-708
references.pmid: 16481637
references.citation: Mol Cell Neurosci. 2007 Nov;36(3):381-91
references.pmid: 17851089
references.citation: Immunol Today. 1992 May;13(5):151-3
references.pmid: 1322675
references.citation: J Allergy Clin Immunol. 2008 Jan;121(1):5-10; quiz 11-2
references.pmid: 18036647
references.citation: Respir Physiol Neurobiol. 2007 May 14;156(2):116-9
references.pmid: 17182290
references.citation: J Allergy Clin Immunol. 2006 Jul;118(1):84-90
references.pmid: 16815142
references.citation: J Auton Nerv Syst. 1982 Mar;5(2):165-76
references.pmid: 7086068
references.citation: Rev Physiol Biochem Pharmacol. 1984;99:1-110
references.pmid: 6695127
references.citation: Respir Physiol. 1993 Jul;93(1):83-96
references.pmid: 8367619
references.citation: Am Rev Respir Dis. 1992 Feb;145(2 Pt 1):332-6
references.pmid: 1736737
references.citation: Neuroscience. 2006 Sep 1;141(3):1533-43
references.pmid: 16765524
references.citation: J Allergy Clin Immunol. 1997 May;99(5):693-8
references.pmid: 9155837
references.citation: Vaccine. 2003 Jun 1;21 Suppl 2:S43-7
references.pmid: 12763682
references.citation: Annu Rev Physiol. 1987;49:557-72
references.pmid: 3551812
references.citation: Am J Respir Cell Mol Biol. 1994 May;10(5):471-80
references.pmid: 8179909
references.citation: Trends Cell Biol. 2001 Sep;11(9):372-7
references.pmid: 11514191
references.citation: Mol Cells. 2011 Jul;32(1):1-5
references.pmid: 21424583
references.citation: Neurochem Res. 2001 Feb;26(2):107-12
references.pmid: 11478736
references.citation: Adv Exp Med Biol. 2010;709:53-66
references.pmid: 21618887
references.citation: Am J Respir Crit Care Med. 1995 Jul;152(1):76-80
references.pmid: 7599866
references.citation: J Appl Physiol (1985). 1990 May;68(5):2042-6
references.pmid: 2361906
references.citation: Thorax. 2005 Dec;60(12):1012-8
references.pmid: 16166100
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12248-52
references.pmid: 16103371
references.citation: J Allergy Clin Immunol. 2007 Jul;120(1):48-55
references.pmid: 17482668
references.citation: Biochim Biophys Acta. 2007 Aug;1772(8):915-27
references.pmid: 17346945
references.citation: J Immunol. 2008 Feb 1;180(3):1878-85
references.pmid: 18209085
references.citation: Respir Physiol. 2001 Mar;125(1-2):47-65
references.pmid: 11240152
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):6155-60
references.pmid: 10823958
references.citation: Eur J Pharmacol. 2006 Mar 8;533(1-3):171-81
references.pmid: 16464447
references.citation: J Biol Chem. 2009 Jan 23;284(4):2275-84
references.pmid: 19049962
references.citation: Allergy. 2001;56 Suppl 66:7-11
references.pmid: 11421935