Pro-inflammatory Phenotype of COPD Fibroblasts not Compatible with Repair in COPD Lung
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.
[1] 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.
[2] Hogg JC, Timens W. The pathology of chronic obstructive pulmonary
disease. Annu Rev Pathol 2009; 4: 435-459.
[3] 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.
[4] Sharafkhaneh A, Hanania NA, Kim V. Pathogenesis of emphysema: from
the bench to the bedside. Proc Am Thorac Soc 2008; 5: 475-477.
[5] Laurell CB, Eriksson S. The electrophoretic alpha-1-globulin pattern in
alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15:
132-140.
[6] 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.
[7] 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.
[8] 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.
[9] 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.
[10] Snider GL, Lucey EC, Stone PJ. State of the art: Animal models of
emphysema. Am Rev Resp Dis 1986, 133:149-169.
[11] 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.
[12] 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.
[13] 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.
[14] Fukuda Y, Masuda Y, and Ishizaki M. Morphogenesis of abnormal elastic
fibers in panacinar and centriacinar emphysema. Hum Pathol 1989,
20:652-659.
[15] 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.
[16] 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.
[17] 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.
[18] 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.
[19] 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.
[20] 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.
[21] 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.
[22] Fink L, Seeger W, Ermert L, Hänze 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.
[23] 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.
[24] 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.
[25] Hallgren O, Nihlberg K, Dahlbäck M, Bjermer L, Eriksson LT, Erjefält
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.
[26] 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.
[27] 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.
[28] 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.
[29] 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.
[30] 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.
[31] 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.
[32] 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.
[33] 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.
[34] 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.
[35] 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.
[36] 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.
[37] Klapperich CM, Bertozzi CR. Global gene expression of cells attached to
a tissue engineering scaffold. Biomaterials. 2004 Nov;25(25):5631-41.
[38] 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.
[39] 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.
[40] 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.
[41] 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.
[42] 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.
[43] 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.
[44] 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.
[45] 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.
[46] 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.
[47] 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
[1] 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.
[2] Hogg JC, Timens W. The pathology of chronic obstructive pulmonary
disease. Annu Rev Pathol 2009; 4: 435-459.
[3] 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.
[4] Sharafkhaneh A, Hanania NA, Kim V. Pathogenesis of emphysema: from
the bench to the bedside. Proc Am Thorac Soc 2008; 5: 475-477.
[5] Laurell CB, Eriksson S. The electrophoretic alpha-1-globulin pattern in
alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15:
132-140.
[6] 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.
[7] 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.
[8] 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.
[9] 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.
[10] Snider GL, Lucey EC, Stone PJ. State of the art: Animal models of
emphysema. Am Rev Resp Dis 1986, 133:149-169.
[11] 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.
[12] 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.
[13] 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.
[14] Fukuda Y, Masuda Y, and Ishizaki M. Morphogenesis of abnormal elastic
fibers in panacinar and centriacinar emphysema. Hum Pathol 1989,
20:652-659.
[15] 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.
[16] 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.
[17] 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.
[18] 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.
[19] 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.
[20] 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.
[21] 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.
[22] Fink L, Seeger W, Ermert L, Hänze 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.
[23] 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.
[24] 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.
[25] Hallgren O, Nihlberg K, Dahlbäck M, Bjermer L, Eriksson LT, Erjefält
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.
[26] 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.
[27] 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.
[28] 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.
[29] 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.
[30] 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.
[31] 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.
[32] 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.
[33] 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.
[34] 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.
[35] 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.
[36] 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.
[37] Klapperich CM, Bertozzi CR. Global gene expression of cells attached to
a tissue engineering scaffold. Biomaterials. 2004 Nov;25(25):5631-41.
[38] 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.
[39] 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.
[40] 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.
[41] 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.
[42] 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.
[43] 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.
[44] 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.
[45] 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.
[46] 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.
[47] 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
@article{"International Journal of Medical, Medicine and Health Sciences:59233", author = "Jing Zhang and Lian Wu and Jie-ming Qu and Chun-xue Bai and Mervyn J Merrilees and Peter N Black", title = "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", keywords = "COPD,pulmonary fibroblasts,pro-inflammatory phenotype, versican, elastin", volume = "5", number = "7", pages = "281-12", }
