title: A comparative study of matrix remodeling in chronic models for COPD; mechanistic insights into the role of TNF-α.
abstract: Remodeling in chronic obstructive pulmonary disease (COPD) has at least two dimensions: small airway wall thickening and destruction of alveolar walls. Recently we showed comparable alterations of the extracellular matrix (ECM) compounds collagen, hyaluoran, and elastin in alveolar and small airway walls of COPD patients. The aim of this study was to characterize and assess similarities in alveolar and small airway wall matrix remodeling in chronic COPD models. From this comparative characterization of matrix remodeling we derived and elaborated underlying mechanisms to the matrix changes reported in COPD. Lung tissue sections of chronic models for COPD, either induced by exposure to cigarette smoke, chronic intratracheal lipopolysaccharide instillation, or local tumor necrosis factor (TNF) expression [surfactant protein C (SPC)-TNFα mice], were stained for elastin, collagen, and hyaluronan. Furthermore TNF-α matrix metalloproteinase (MMP)-2, -9, and -12 mRNA expression was analyzed using qPCR and localized using immunohistochemistry. Both collagen and hyaluronan were increased in alveolar and small airway walls of all three models. Interestingly, elastin contents were differentially affected, with a decrease in both alveolar and airway walls in SPC-TNFα mice. Furthermore TNF-α and MMP-2 and -9 mRNA and protein levels were found to be increased in alveolar walls and around airway walls only in SPC-TNFα mice. We show that only SPC-TNFα mice show changes in elastin remodeling that are comparable to what has been observed in COPD patients. This reveals that the SPC-TNFα model is a suitable model to study processes underlying matrix remodeling and in particular elastin breakdown as seen in COPD. Furthermore we indicate a possible role for MMP-2 and MMP-9 in the breakdown of elastin in airways and alveoli of SPC-TNFα mice.
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands; irene.eurlings@maastrichtuniversity.nl.
authors.forename: Irene M J
authors.initials: IM
authors.lastname: Eurlings
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands;
authors.forename: Mieke A
authors.initials: MA
authors.lastname: Dentener
authors.affiliation: Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and.
authors.forename: Evi M
authors.initials: EM
authors.lastname: Mercken
authors.affiliation: Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Ken R
authors.initials: KR
authors.lastname: Bracke
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands;
authors.forename: Juanita H J
authors.initials: JH
authors.lastname: Vernooy
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands;
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands;
authors.forename: Niki L
authors.initials: NL
authors.lastname: Reynaert
mesh_terms: D056151:Airway Remodeling / Q000276:immunology; D000818:Animals; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D024022:Fibrillar Collagens / Q000378:metabolism; D015870:Gene Expression; D006820:Hyaluronic Acid / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D024022:Fibrillar Collagens; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D004549:Elastin; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: chronic obstructive pulmonary disease; elastin; mice model; tumor necrosis factor-α
references.citation: Am J Pathol. 2012 Apr;180(4):1413-30
references.pmid: 22322299
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1149-57
references.pmid: 18408070
references.citation: Eur Respir J. 2005 Jan;25(1):15-22
references.pmid: 15640318
references.citation: Respir Res. 2008 May 18;9:41
references.pmid: 18485243
references.citation: Am J Respir Cell Mol Biol. 2010 Jun;42(6):753-61
references.pmid: 19675307
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Jan;280(1):L39-49
references.pmid: 11133493
references.citation: Clin Sci (Lond). 2014 Feb;126(3):207-21
references.pmid: 23875733
references.citation: BMC Pulm Med. 2014 May 26;14:90
references.pmid: 24886452
references.citation: Thorax. 2005 Feb;60(2):114-9
references.pmid: 15681498
references.citation: Am J Clin Pathol. 2006 Nov;126(5):725-35
references.pmid: 17111536
references.citation: Chest. 2002 Dec;122(6 Suppl):271S-275S
references.pmid: 12475796
references.citation: Am J Respir Crit Care Med. 1998 Aug;158(2):555-64
references.pmid: 9700135
references.citation: Eur Respir J. 2008 May;31(5):998-1004
references.pmid: 18216063
references.citation: Eur Respir J. 2012 Dec;40(6):1362-73
references.pmid: 22496324
references.citation: Cancer Res. 2009 Sep 15;69(18):7252-61
references.pmid: 19706765
references.citation: Am J Respir Crit Care Med. 2002 Sep 15;166(6):849-54
references.pmid: 12231496
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Jul 1;305(1):L15-22
references.pmid: 23624789
references.citation: Am J Respir Crit Care Med. 1996 Feb;153(2):530-4
references.pmid: 8564092
references.citation: Br J Pharmacol. 2009 Aug;157(7):1111-27
references.pmid: 19508395
references.citation: Respir Res. 2010 May 11;11:55
references.pmid: 20459817
references.citation: Eur Respir J. 2005 Aug;26(2):204-13
references.pmid: 16055867
references.citation: J Appl Physiol (1985). 2005 Feb;98(2):503-11
references.pmid: 15465889
references.citation: Thorax. 2006 Mar;61(3):196-201
references.pmid: 16308335
references.citation: Int Arch Allergy Immunol. 2005 Oct;138(2):169-79
references.pmid: 16192742
references.citation: N Engl J Med. 2011 Oct 27;365(17):1567-75
references.pmid: 22029978
references.citation: Physiol Rev. 2011 Jan;91(1):221-64
references.pmid: 21248167
references.citation: Am J Respir Cell Mol Biol. 2008 Nov;39(5):584-90
references.pmid: 18539952
references.citation: J Biol Chem. 2008 May 16;283(20):13652-65
references.pmid: 18359769
references.citation: Am J Respir Cell Mol Biol. 2002 Jan;26(1):152-9
references.pmid: 11751215
references.citation: Thorax. 1994 Apr;49(4):319-26
references.pmid: 8202900
references.citation: Respirology. 2010 Aug;15(6):930-8
references.pmid: 20630030
references.citation: Matrix Biol. 2013 Mar 11;32(2):86-94
references.pmid: 23160093
references.citation: Am J Respir Crit Care Med. 2010 Feb 15;181(4):394-418
references.pmid: 20130146
references.citation: Thorax. 2007 Aug;62(8):706-13
references.pmid: 17311841
references.citation: Histol Histopathol. 2013 Feb;28(2):269-76
references.pmid: 23275309
references.citation: Pulm Pharmacol Ther. 2012 Apr;25(2):169-77
references.pmid: 22306193
references.citation: Am J Respir Crit Care Med. 2005 Jun 15;171(12):1363-70
references.pmid: 15805183
references.citation: J Clin Invest. 1995 Jul;96(1):250-9
references.pmid: 7542280