help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on June 7, 2004, doi:10.1164/rccm.200404-511OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200404-511OCv1
170/5/492    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Churg, A.
Right arrow Articles by Wright, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Churg, A.
Right arrow Articles by Wright, J. L.
American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 492-498, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200404-511OC

Original Article

Tumor Necrosis Factor-{alpha} Drives 70% of Cigarette Smoke–induced Emphysema in the Mouse

Andrew Churg, Rong D. Wang, Hsin Tai, Xiaoshan Wang, Changshi Xie and Joanne L. Wright

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Andrew Churg, M.D., Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5 Canada. E-mail: achurg{at}interchange.ubc.ca

Mice lacking tumor necrosis factor-{alpha} (TNF-{alpha}) receptors (TNFRKO mice) do not develop an inflammatory infiltrate or matrix breakdown after a single acute cigarette smoke exposure. To determine the role of TNF-{alpha} in the long-term development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice demonstrated an 11% increase in mean linear intercept; wild-type mice had a 38% increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in lavage fluid. Whole lung matrix metalloprotease (MMP)-2, MMP-9, MMP-12, MMP-13, and matrix type-1 (MT1)-MMP proteins were increased in wild-type mice, but smaller increases in MMP-12, MMP-13, and MT1-MMP were also seen in TNFRKO mice. Lavage matrix breakdown products were elevated in wild-type mice and only partially reduced by anti-neutrophil antibody, implying both neutrophil- and non–neutrophil-mediated matrix breakdown. We conclude that TNF-{alpha}–mediated processes, probably driving neutrophil influx, are responsible for approximately 70% of airspace enlargement and the majority of inflammatory cell influx/matrix breakdown in the mouse model. TNF-{alpha} causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second TNF-{alpha}–independent process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.

Key Words: emphysema • macrophage metalloelastase-12 • matrix metalloprotease • tumor necrosis factor-{alpha}




This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. L. Wright, M. Cosio, and A. Churg
Animal models of chronic obstructive pulmonary disease
Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L1 - L15.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. Xu, F. Xu, and E. Barrett
Metalloelastase in lungs and alveolar macrophages is modulated by extracellular substance P in mice
Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L162 - L170.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
K. F. Chung and I. M. Adcock
Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction
Eur. Respir. J., June 1, 2008; 31(6): 1334 - 1356.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
T. R. Medler, D. N. Petrusca, P. J. Lee, W. C. Hubbard, E. V. Berdyshev, J. Skirball, K. Kamocki, E. Schuchman, R. M. Tuder, and I. Petrache
Apoptotic Sphingolipid Signaling by Ceramides in Lung Endothelial Cells
Am. J. Respir. Cell Mol. Biol., June 1, 2008; 38(6): 639 - 646.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
R. Summer, F. F. Little, N. Ouchi, Y. Takemura, T. Aprahamian, D. Dwyer, K. Fitzsimmons, B. Suki, H. Parameswaran, A. Fine, et al.
Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice
Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1035 - L1042.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
V. Kim, T. J. Rogers, and G. J. Criner
New Concepts in the Pathobiology of Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, May 1, 2008; 5(4): 478 - 485.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
M. R. Gingo, L. J. Silveira, Y. E. Miller, A. L. Friedlander, G. P. Cosgrove, E. D. Chan, L. A. Maier, and R. P. Bowler
Tumour necrosis factor gene polymorphisms are associated with COPD
Eur. Respir. J., May 1, 2008; 31(5): 1005 - 1012.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
H. Yao, I. Edirisinghe, S.-R. Yang, S. Rajendrasozhan, A. Kode, S. Caito, D. Adenuga, and I. Rahman
Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice
Am. J. Pathol., May 1, 2008; 172(5): 1222 - 1237.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
A. Churg, M. Cosio, and J. L. Wright
Mechanisms of cigarette smoke-induced COPD: insights from animal models
Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L612 - L631.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
A. Elizur, T. L. Adair-Kirk, D. G. Kelley, G. L. Griffin, D. E. deMello, and R. M. Senior
Tumor Necrosis Factor-{alpha} from Macrophages Enhances LPS-Induced Clara Cell Expression of Keratinocyte-Derived Chemokine
Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 8 - 15.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
F. Facchinetti, F. Amadei, P. Geppetti, F. Tarantini, C. Di Serio, A. Dragotto, P. M. Gigli, S. Catinella, M. Civelli, and R. Patacchini
{alpha},beta-Unsaturated Aldehydes in Cigarette Smoke Release Inflammatory Mediators from Human Macrophages
Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 617 - 623.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
R A Stockley
Biomarkers in COPD: time for a deep breath
Thorax, August 1, 2007; 62(8): 657 - 660.
[Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
A. Churg, X. Wang, R. D. Wang, S. C. Meixner, E. L. G. Pryzdial, and J. L. Wright
{alpha}1-Antitrypsin Suppresses TNF-{alpha} and MMP-12 Production by Cigarette Smoke-Stimulated Macrophages
Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 144 - 151.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
R. M. Tuder and I. Petrache
Molecular Multitasking in the Airspace: {alpha}1-Antitrypsin Takes on Thrombin and Plasmin
Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 130 - 134.
[Full Text] [PDF]

Home page
 ThoraxHome page
A. Churg, R. Wang, X. Wang, P.-O. Onnervik, K. Thim, and J. L Wright
Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs
Thorax, August 1, 2007; 62(8): 706 - 713.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
T. Yoshida and R. M. Tuder
Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease
Physiol Rev, July 1, 2007; 87(3): 1047 - 1082.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. J. Barnes
Unexpected Failure of Anti-Tumor Necrosis Factor Therapy in Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., May 1, 2007; 175(9): 866 - 867.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. I. Rennard, C. Fogarty, S. Kelsen, W. Long, J. Ramsdell, J. Allison, D. Mahler, C. Saadeh, T. Siler, P. Snell, et al.
The Safety and Efficacy of Infliximab in Moderate to Severe Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., May 1, 2007; 175(9): 926 - 934.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
H.-Y. Cho, D. L. Morgan, A. K. Bauer, and S. R. Kleeberger
Signal Transduction Pathways of Tumor Necrosis Factor-mediated Lung Injury Induced by Ozone in Mice
Am. J. Respir. Crit. Care Med., April 15, 2007; 175(8): 829 - 839.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
J. L. Wright and A. Churg
Current Concepts in Mechanisms of Emphysema
Toxicol Pathol, January 1, 2007; 35(1): 111 - 115.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
G. Tanaka, A. J. Sandford, K. Burkett, J. E. Connett, N. R. Anthonisen, P. D. Pare, and J-Q. He
Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers
Eur. Respir. J., January 1, 2007; 29(1): 34 - 41.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
R. Forteza, S. M. Casalino-Matsuda, M. E. Monzon, E. Fries, M. S. Rugg, C. M. Milner, and A. J. Day
TSG-6 Potentiates the Antitissue Kallikrein Activity of Inter-{alpha}-inhibitor through Bikunin Release
Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 20 - 31.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. L. Wright, H. Tai, R. Wang, X. Wang, and A. Churg
Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-{alpha} signaling
Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L125 - L133.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
A. I. D'hulst, K. R. Bracke, T. Maes, J. L. De Bleecker, R. A. Pauwels, G. F. Joos, and G. G. Brusselle
Role of tumour necrosis factor-{alpha} receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema
Eur. Respir. J., July 1, 2006; 28(1): 102 - 112.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
C. S. Berenson, C. T. Wrona, L. J. Grove, J. Maloney, M. A. Garlipp, P. K. Wallace, C. C. Stewart, and S. Sethi
Impaired Alveolar Macrophage Response to Haemophilus Antigens in Chronic Obstructive Lung Disease
Am. J. Respir. Crit. Care Med., July 1, 2006; 174(1): 31 - 40.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
M A Dentener, R Louis, R H E Cloots, M Henket, and E F M Wouters
Differences in local versus systemic TNF{alpha} production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNF{alpha} release
Thorax, June 1, 2006; 61(6): 478 - 484.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
H. Chen, M. J. Hansen, J. E. Jones, R. Vlahos, S. Bozinovski, G. P. Anderson, and M. J. Morris
Cigarette Smoke Exposure Reprograms the Hypothalamic Neuropeptide Y Axis to Promote Weight Loss
Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1248 - 1254.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
O. Bonneau, D. Wyss, S. Ferretti, C. Blaydon, C. S. Stevenson, and A. Trifilieff
Effect of adenosine A2A receptor activation in murine models of respiratory disorders
Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L1036 - L1043.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
E. R. Weibel, H. Parameswaran, A. Majumdar, S. Ito, A. M. Alencar, B. Suki, W. Mitzner, C. C. W. Hsia, H. Fehrenbach, and J. P. Butler
Morphological Quantitation of Emphysema: A Debate
J Appl Physiol, April 1, 2006; 100(4): 1419 - 1421.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
P T G Elkington and J S Friedland
Matrix metalloproteinases in destructive pulmonary pathology
Thorax, March 1, 2006; 61(3): 259 - 266.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
S. Kasagi, K. Seyama, H. Mori, S. Souma, T. Sato, T. Akiyoshi, H. Suganuma, and Y. Fukuchi
Tomato juice prevents senescence-accelerated mouse P1 strain from developing emphysema induced by chronic exposure to tobacco smoke
Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L396 - L404.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
H. Parameswaran, A. Majumdar, S. Ito, A. M. Alencar, and B. Suki
Quantitative characterization of airspace enlargement in emphysema
J Appl Physiol, January 1, 2006; 100(1): 186 - 193.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. T. G. Elkington, R. K. Nuttall, J. J. Boyle, C. M. O'Kane, D. E. Horncastle, D. R. Edwards, and J. S. Friedland
Mycobacterium tuberculosis, but Not Vaccine BCG, Specifically Upregulates Matrix Metalloproteinase-1
Am. J. Respir. Crit. Care Med., December 15, 2005; 172(12): 1596 - 1604.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J.-H. Lee, D.-S. Lee, E.-K. Kim, K.-H. Choe, Y.-M. Oh, T.-S. Shim, S.-E. Kim, Y.-S. Lee, and S.-D. Lee
Simvastatin Inhibits Cigarette Smoking-induced Emphysema and Pulmonary Hypertension in Rat Lungs
Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 987 - 993.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. A. Martorana, R. Beume, M. Lucattelli, L. Wollin, and G. Lungarella
Roflumilast Fully Prevents Emphysema in Mice Chronically Exposed to Cigarette Smoke
Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 848 - 853.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
H. van der Vaart, G. H. Koeter, D. S. Postma, H. F. Kauffman, and N. H. T. ten Hacken
First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 465 - 469.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
T. H. Thatcher, N. A. McHugh, R. W. Egan, R. W. Chapman, J. A. Hey, C. K. Turner, M. R. Redonnet, K. E. Seweryniak, P. J. Sime, and R. P. Phipps
Role of CXCR2 in cigarette smoke-induced lung inflammation
Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L322 - L328.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
L. Fabbri, S. P. Peters, I. Pavord, S. E. Wenzel, S. C. Lazarus, W. MacNee, F. Lemaire, and E. Abraham
Allergic Rhinitis, Asthma, Airway Biology, and Chronic Obstructive Pulmonary Disease in AJRCCM in 2004
Am. J. Respir. Crit. Care Med., April 1, 2005; 171(7): 686 - 698.
[Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
P. J. Barnes
Mediators of Chronic Obstructive Pulmonary Disease
Pharmacol. Rev., December 1, 2004; 56(4): 515 - 548.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2004 American Thoracic Society 		  Solid Organ Transplant for the Intensivist 2008