title: Human neutrophil elastase-mediated goblet cell metaplasia is attenuated in TACE-deficient mice.
abstract: Neutrophilic inflammation is associated with chronic airway diseases. It has been observed that human neutrophil elastase (HNE), which is secreted by active neutrophils during inflammation, induces both mucin overproduction and goblet cell metaplasia. Several in vitro studies suggest that tumor necrosis factor-α converting enzyme (TACE) regulates the signaling axis that mediates HNE-induced mucin overproduction; however, it is unknown whether TACE performs a similar function in HNE-induced goblet cell metaplasia in vivo. We conducted this study to determine whether the inactivation of Tace gene expression attenuates HNE-induced goblet cell metaplasia in mice. Deletion of Tace is lethal shortly after birth in mice; therefore, we utilized Tace(flox/flox)R26CreER(+/-) mice and induced conditional deletion of Tace using a tamoxifen injection. Wild-type mice were given tamoxifen to control for its effect. Tace conditional deletion mice and wild-type mice were exposed to HNE via nasal instillation three times at 3-day intervals, and the lungs were harvested on day 11 after initial HNE exposure. Using periodic acid-Schiff staining and MUC5AC immunohistochemical staining to visualize goblet cells in the lungs, we found that HNE induced goblet cell metaplasia in the wild-type mice and that HNE-induced goblet cell metaplasia was significantly attenuated in the Tace conditional deletion mice. These findings suggest that TACE could be a potential target in the treatment of goblet cell metaplasia in patients with chronic airway diseases.
authors.affiliation: Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Park
authors.forename: Asma S
authors.initials: AS
authors.lastname: Sharif
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiomi
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.forename: David I
authors.initials: DI
authors.lastname: Kasahara
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
authors.forename: Judith
authors.initials: J
authors.lastname: Voynow
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Drazen
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency* / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D020397:Goblet Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019272:Leukocyte Elastase / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D013629:Tamoxifen; D019272:Leukocyte Elastase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: airway epithelium; airway mucin; chronic airway disease; neutrophilic inflammation
references.citation: Cytokine. 2009 Jun;46(3):309-15
references.pmid: 19346138
references.citation: Am J Pathol. 2007 Dec;171(6):1822-30
references.pmid: 18055557
references.citation: Am J Respir Cell Mol Biol. 2011 Aug;45(2):376-85
references.pmid: 21097655
references.citation: Respir Care. 2007 Sep;52(9):1134-46; discussion 1146-9
references.pmid: 17716382
references.citation: Biochem J. 2000 Apr 1;347 Pt 1:131-8
references.pmid: 10727411
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Apr;284(4):L671-9
references.pmid: 12495942
references.citation: Am J Respir Cell Mol Biol. 2012 Sep;47(3):349-57
references.pmid: 22493011
references.citation: J Immunol. 2009 Jun 15;182(12):7408-14
references.pmid: 19494263
references.citation: Science. 1998 Nov 13;282(5392):1281-4
references.pmid: 9812885
references.citation: Nat Rev Mol Cell Biol. 2005 Jan;6(1):32-43
references.pmid: 15688065
references.citation: Trends Immunol. 2011 Aug;32(8):380-7
references.pmid: 21752713
references.citation: Am J Pathol. 2005 Sep;167(3):651-61
references.pmid: 16127146
references.citation: Eur Respir J. 2010 May;35(5):1164-71
references.pmid: 19897560
references.citation: FASEB J. 2000 Jul;14(10):1362-74
references.pmid: 10877829
references.citation: Am J Respir Cell Mol Biol. 2002 Apr;26(4):447-52
references.pmid: 11919081
references.citation: Mol Biol Cell. 2009 Mar;20(6):1785-94
references.pmid: 19158376
references.citation: Chest. 2009 Feb;135(2):505-512
references.pmid: 19201713
references.citation: Am J Respir Cell Mol Biol. 2007 Dec;37(6):691-8
references.pmid: 17600314
references.citation: Am Rev Respir Dis. 1992 Dec;146(6):1430-3
references.pmid: 1280928
references.citation: J Allergy Clin Immunol. 1995 Apr;95(4):843-52
references.pmid: 7722165
references.citation: J Immunol. 2007 Sep 1;179(5):2686-9
references.pmid: 17709479
references.citation: Ann Allergy Asthma Immunol. 2009 Oct;103(4):295-303
references.pmid: 19852193
references.citation: Thorax. 2004 Nov;59(11):992-6
references.pmid: 15516478
references.citation: Ann N Y Acad Sci. 1991;624:286-96
references.pmid: 2064229
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Sep;299(3):L345-52
references.pmid: 20543006
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Mar;300(3):L414-21
references.pmid: 21224214
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Dec;287(6):L1293-302
references.pmid: 15273079
references.citation: J Clin Invest. 2006 Feb;116(2):306-8
references.pmid: 16453018
references.citation: Proc Natl Acad Sci U S A. 1987 Dec;84(24):9304-8
references.pmid: 3480544
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 Sep;283(3):L531-40
references.pmid: 12169572
references.citation: Chest. 2002 May;121(5 Suppl):142S-150S
references.pmid: 12010843
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):767-72
references.pmid: 15640347
references.citation: Annu Rev Physiol. 2008;70:405-29
references.pmid: 17961085