Commenced in January 2007
Paper Count: 30172
Pro-inflammatory Phenotype of COPD Fibroblasts not Compatible with Repair in COPD Lung
Abstract:COPD is characterized by loss of elastic fibers from small airways and alveolar walls, with the decrease in elastin increasing with disease severity. It is unclear why there is a lack of repair of elastic fibers. We have examined fibroblasts cultured from lung tissue from normal and COPD subjects to determine if the secretory profile explains lack of tissue repair. In this study, fibroblasts were cultured from lung parenchyma of bronchial carcinoma patients with varying degrees of COPD; controls (non-COPD, n=5), mild COPD (GOLD 1, n=5) and moderate-severe COPD (GOLD 2-3, n=12). Measurements were made of proliferation, senescence-associated beta-galactosidase-1, mRNA expression of IL-6, IL-8, MMP-1, tropoelastin and versican, and protein levels for IL-6, IL-8, PGE2, tropoelastin, insoluble elastin, and versican. It was found that GOLD 2-3 fibroblasts proliferated more slowly (p<0.01) and had higher levels of senescence-associated beta-galactosidase-1 (p<0.001) than controls (non-COPD). GOLD 2-3 fibroblasts showed significant increases in mRNA and/or protein for IL-6, IL-8, MMP-1, PGE2, versican (p<0.01) and tropoelastin (p<0.05). mRNA expression and/or protein levels of tropoelastin (p<0.01), versican (p<0.02), IL-6 (p<0.05) and IL-8 (p<0.05) were negatively correlated with FEV1%. Insoluble elastin was not increased. In summary, fibroblasts from moderate to severe COPD subjects display a secretory phenotype with up-regulation of inflammatory molecules including the matrix proteoglycan versican, and increased soluble, but not insoluble, elastin. Versican inhibits assembly of tropoelastin into insoluble elastin and we conclude that the pro-inflammatory phenotype of COPD fibroblasts it is not compatible with repair elastic fibers.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1074739Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 1227
 Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airways obstruction in chronic obstructive lung disease. N Engl J Med 1968; 278; 1355-60.
 Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 2009; 4: 435-459.
 Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 2):S28-38. Review. PubMed PMID:11734464.
 Sharafkhaneh A, Hanania NA, Kim V. Pathogenesis of emphysema: from the bench to the bedside. Proc Am Thorac Soc 2008; 5: 475-477.
 Laurell CB, Eriksson S. The electrophoretic alpha-1-globulin pattern in alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15: 132-140.
 Stone PJ, Calore JD, McGowan SE, Bernardo J, Snider GL, Franzblau C. Smokers do not have less functional alpha 1-protease inhibitor in their lower respiratory tracts than nonsmokers. Chest. 1983 May;83(5 Suppl):65S-66S. PubMed PMID:6601572.
 Holz O, Z├╝hlke I, Jaksztat E, et al. Lung fibroblasts from patients with emphysema show a reduced proliferation rate in culture. Eur Respir J 2004; 24: 575-579.
 Togo S, Holz O, Liu X, et al. Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms. Am J Respir Crit Care Med 2008; 178: 248-260.
 Shapiro SD, Endicott SK, Province MA, Pierce JA, Campbell EJ. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons related radiocarbon. J Clin Invest 1991; 87: 1828-34.
 Snider GL, Lucey EC, Stone PJ. State of the art: Animal models of emphysema. Am Rev Resp Dis 1986, 133:149-169.
 Chambers RC and Laurent GJ. The lung. In Extracellular Matrix, Volume 1, Tissue Function. Edited by Comper WD. The Netherlands, Harwood Academic Publishers GmbH; 1996: 378-409.
 Morris SM, Stone PJ, Snider GL, Albright T, Franzblau C. Ultrastructural changes in hamster lung four hours to twenty-four days after exposure to elastase. Anat Rec 1981, 201:523-535.
 Osman M, Cantor JO, Roffman S, Keller S, Turino GM, Mandl I. Cigarette smoke impairs elastin resynthesis in lungs of hampsters with elastase-induced emphysema. Am Rev Resp Dis 1985, 132:640-643.
 Fukuda Y, Masuda Y, and Ishizaki M. Morphogenesis of abnormal elastic fibers in panacinar and centriacinar emphysema. Hum Pathol 1989, 20:652-659.
 Deslee G, Woods JC, Moore CM, Liu L, Conradi SH, Milne M, Gierada DS, Pierce J, Patterson A, Lewit RA, Battaile JT, Holtzman MJ, Hogg JC, Pierce RA. Elastin expression in very severe human COPD. Eur Respir J. 2009 Aug;34(2):324-31.
 Merrilees MJ, Ching PS, Beaumont B, Hinek A, Wight TN, Black PN. Changes in elastin, elastin binding protein and versican in alveoli in chronic obstructive pulmonary disease. Respir Res. 2008 May 18;9:41.
 Black PN, Ching PS, Beaumont B, Ranasinghe S, Taylor G, Merrilees MJ. Changes in elastic fibers in the small airways and alveoli in COPD. Eur Respir J. 2008 May;31(5):998-1004. Epub 2008 Jan 23.
 Hinek A, Mecham RP, Keeley F, Rabinovitch M. Impaired elastin fiber assembly related to reduced 67-kD elastin-binding protein in fetal lamb ductus arteriosus and in cultured aortic smooth muscle cells treated with chondroitin sulfate. J Clin Invest. 1991;88:2083-94.
 Hinek A, Smith AC, Cutiongco EM, Callahan JW, Gripp KW, Weksberg R. Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein. Am J Hum Genet. 2000;66:859-72.
 Huang R, Merrilees MJ, Braun K, Beaumont B, Lemire J, Clowes AW, Hinek A, Wight TN: Inhibition of versican synthesis by antisense alters smooth muscle cell phenotype and induces elastic fiber formation in vitro and in neointima after vessel injury. Circ Res. 2006;98:370-377.
 Al-Nasiry S, Geusens N, Hanssens M, Luyten C, Pijnenborg R. The use of Alamar Blue assay for quantitative analysis of viability, migration and invasion of choriocarcinoma cells. Hum Reprod 2007;22:1304-9.
 Fink L, Seeger W, Ermert L, H├ñnze J, Stahl U, Grimminger F, Kummer W, Bohle RM. Real-time quantitative RT-PCR after laser-assisted cell picking. Nat Med. 1998 Nov;4(11):1329-33. PubMed PMID: 9809560.
 Lemire JM, Merrilees MJ, Braun KR, Wight TN. Over-expression of the V3 variant of versican alters arterial smooth muscle cell adhesion, migration, and proliferation in vitro. J Cell Physiol. 2002;190:38-45.
 Merrilees MJ, Lemire JM, Fischer JW, Kinsella MG, Braun KR, Clowes AW, Wight TN. Retrovirally mediated over-expression of versican V3 by arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury. Circ Res. 2002;90:481-7.
 Hallgren O, Nihlberg K, Dahlb├ñck M, Bjermer L, Eriksson LT, Erjef├ñlt JS, Löfdahl CG, Westergren-Thorsson G. Altered fibroblast proteoglycan production in COPD. Respir Res. 2010 May 11;11:55. PubMed PMID: 20459817; PubMed Central PMCID: PMC2886021.
 Asano K, Shikama Y, Shibuya Y, Nakajima H, Kanai K, Yamada N, Suzaki H. Suppressive activity of tiotropium bromide on matrix metalloproteinase production from lung fibroblasts in vitro. Int J Chron Obstruct Pulmon Dis. 2008;3(4):781-9. PubMed PMID: 19281093; PubMed Central PMCID: PMC2650607.
 Asano K, Shikama Y, Shoji N, Hirano K, Suzaki H, Nakajima H. Tiotropium bromide inhibits TGF-β-induced MMP production from lung fibroblasts by interfering with Smad and MAPK pathways in vitro. Int J Chron Obstruct Pulmon Dis. 2010 Sep 7;5:277-86. PubMed PMID: 20856827; PubMed Central PMCID: PMC2939683.
 Jin-Yong Hwang, Pamela Y. Johnson, Kathleen R. Braun, Alexander Hinek, Jens W. Fischer, Kevin D. O-Brien, Alexander W. Clowes, Mervyn J. Merrilees, Thomas N. Wight. Retrovirally-mediated overexpression of glycosaminoglycan-deficient biglycan in arterial smooth muscle cells Induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury. American Journal of Pathology 2008; 173:1919-1928.
 Hinek A, Braun KR, Liu K, Wang Y, Wight T: Retrovirally mediated overexpression of versican V3 reverses impaired elastogenesis and heightened proliferation exhibited by fibroblasts from Costello syndrome and Hurler disease patients. Am J Pathol 2004, 164:119-131.
 Maquart F-X, Pasco S, Ramont L, Hornebeck W, Monboisse J-C: An introduction to matrikines: extracellular matrix-derived peptides which regulate cell activity. Implication in tumor invasion. Crit Rev Oncol/Hemat 2004, 49:199-202.
 Eddahibi S, Chaouat A, Tu L, Chouaid C, Weitzenblum E, Housset B, et al. Interleukin-6 gene polymorphism confers susceptibility to pulmonary hypertension in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2006; 3: 475-6.
 Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care. Med. 1996; 153: 530-4.
 Ko FW, Leung TF, Wong GW, Ngai J, To KW, Ng S, et al. Measurement of tumor necrosis factor-alpha, leukotriene B4, and interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis. 2009; 4: 79-86.
 Lee TM, Lin MS, Chang NC. Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am. J. Cardiol. 2008; 101: 530-5.
 Le Bellego F, Perera H, Plante S, Chakir J, Hamid Q, Ludwig MS. Mechanical strain increases cytokine and chemokine production in bronchial fibroblasts from asthmatic patients. Allergy. 2009 Jan;64(1):32-9. Epub 2008 Dec 12.
 Beikler T, Peters U, Prior K, Eisenacher M, Flemmig TF. Gene expression in periodontal tissues following treatment. BMC Med Genomics. 2008 Jul 7;1:30.
 Klapperich CM, Bertozzi CR. Global gene expression of cells attached to a tissue engineering scaffold. Biomaterials. 2004 Nov;25(25):5631-41.
 Kim S, Takahashi H, Lin W-W, Descargues P, Grivennikov S, Kim Y, Luo J-L, Karin M. Carcinoma-produced factors activate myeloid cells through TRL2 to stimulate metastasis. Nature 2009;547:102-106.
 Seidelmann SB, Kuo C, Pleskac N, Molina J, Sayers S, Li R, Zhou J, Johnson P, Braun K, Chan C, Teupser D, Breslow JL, Wight TN, Tall AR, Welch CL. Athsq1 is an atherosclerosis modifier locus with dramatic effects on lesion area and prominent accumulation of versican. Arterioscler Thromb Vasc Biol. 2008;28:2180-6.
 Zheng PS, Vais D, Lapierre D, Liang YY, Lee V, Yang BL, Yang BB. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation. J Cell Sci. 2004;117:5887-95.
 Potter-Perigo S, Johnson PY, Evanko SP, Chan CK, Braun KR, Wilkinson TS, Altman LC, Wight TN. Polyinosine-polycytidylic acid stimulates versican accumulation in the extracellular matrix promoting monocyte adhesion. Am J Respir Cell Mol Biol. 2010;43:109-120.
 Evanko SP, Potter-Perigo S, Johnson PY, Wight TN. Organization of hyaluronan and versican in the extracellular matrix of human fibroblasts treated with the viral mimetic Poly I:C. J Histochem Cytochem. 2009;57:1041-1060.
 White ES, Atrasz RG, Dickie EG, Aronoff DM, Stambolic V, Mak TW, Moore BB, Peters-Golden M. Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity. Am J Respir Cell Mol Biol 2005;32:135-141.
 Lama V, Moore BB, Christensen P, Toews GB, Peters-Golden M. Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent. Am J Respir Cell Mol Biol 2002;27:752-758.
 Liu X, Ostrom RS, Insel PA. cAMP-elevating agents and adenylyl cyclase overexpression promote an antifibrotic phenotype in pulmonary fibroblasts. Am J Physiol Cell Physiol 2004;286:C1089-C1099.
 M├╝ller KC, Welker L, Paasch K, Feindt B, Erpenbeck VJ, Hohlfeld JM, Krug N, Nakashima M, Branscheid D, Magnussen H, Jörres RA, Holz O. Lung fibroblasts from patients with emphysema show markers of senescence in vitro. Respir Res. 2006 Feb 21;7:32. PubMed PMID: 16504044; PubMed Central PMCID: PMC1435750.
 Merrilees MJ, Beaumont BW, Braun KR, Thomas AC, Kang I, Hinek A, Passi A,Wight TN. Neointima formed by arterial smooth muscle cells expressing versican variant v3 is resistant to lipid and macrophage accumulation. Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1309-16. Epub 2011 Mar 24. PubMed PMID: 21441139