help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on April 10, 2003, doi:10.1164/rccm.200302-203OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200302-203OCv1
168/2/199    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 168. pp. 199-207, (2003)
© 2003 American Thoracic Society

Original Article

{alpha}-1-Antitrypsin Ameliorates Cigarette Smoke–induced Emphysema in the Mouse

Andrew Churg, Rong D. 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, Canada V6T 2B5. E-mail: achurg{at}interchange.ubc.ca

Serine elastase inhibitors have been proposed as a treatment for cigarette smoke–induced emphysema, but little is known about whether such agents actually are effective. We recently reported that a synthetic serine elastase inhibitor, ZD0892, provided some protection against emphysema in a guinea pig model. For these experiments, we used transgenic mice that expressed extremely low levels of human {alpha}-1-antitrypsin (A1AT) but were tolerant of exogenous human A1AT. Mice were exposed to daily cigarette smoke for up to 6 months; some animals received 20 mg of human A1AT (Prolastin) every 48 hours. Treatment with A1AT produced an approximate twofold increase in serum A1AT levels and elastase inhibitory capacity and abolished smoke-induced elevations in lavage neutrophils and matrix breakdown products (desmosine and hydroxyproline) measured from 2 to 30 days of smoke exposure. A1AT oxidized to remove antiproteolytic activity did not increase serum elastase inhibitory capacity but did prevent neutrophil influx. Treatment with A1AT for 6 months provided 63% protection against increased airspace size (emphysema) and abolished smoke-mediated increases in plasma tumor necrosis factor-{alpha}. We conclude that A1AT therapy ameliorates smoke-induced inflammation and matrix breakdown, possibly via an antiinflammatory mechanism related to tumor necrosis factor-{alpha} suppression, and provides partial protection against emphysema.

Key Words: neutrophil • {alpha}-1-antitrypsin • cigarette smoke • emphysema




This article has been cited by other articles:


Home page
 Am. J. Respir. Cell Mol. Bio.Home page
R. M. Tuder, J. H. Yun, and B. B. Graham
Cigarette Smoke Triggers Code Red: p21CIP1/WAF1/SDI1 Switches on Danger Responses in the Lung
Am. J. Respir. Cell Mol. Biol., July 1, 2008; 39(1): 1 - 6.
[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. Physiol. Lung Cell. Mol. Physiol.Home page
R. D. Bland, R. Ertsey, L. M. Mokres, L. Xu, B. E. Jacobson, S. Jiang, C. M. Alvira, M. Rabinovitch, E. S. Shinwell, and A. Dixit
Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice.: Prelude to defective alveolar septation during lung development?
Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L3 - L14.
[Abstract] [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
 J. Biol. Chem.Home page
S. M. Janciauskiene, I. M. Nita, and T. Stevens
{alpha}1-Antitrypsin, Old Dog, New Tricks: {alpha}1-ANTITRYPSIN EXERTS IN VITRO ANTI-INFLAMMATORY ACTIVITY IN HUMAN MONOCYTES BY ELEVATING cAMP
J. Biol. Chem., March 23, 2007; 282(12): 8573 - 8582.
[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
 Am. J. Pathol.Home page
I. Petrache, I. Fijalkowska, T. R. Medler, J. Skirball, P. Cruz, L. Zhen, H. I. Petrache, T. R. Flotte, and R. M. Tuder
{alpha}-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis
Am. J. Pathol., October 1, 2006; 169(4): 1155 - 1166.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
T. H. March, J. A. Wilder, D. C. Esparza, P. Y. Cossey, L. F. Blair, L. K. Herrera, J. D. McDonald, M. J. Campen, J. L. Mauderly, and J. Seagrave
Modulators of Cigarette Smoke-Induced Pulmonary Emphysema in A/J Mice
Toxicol. Sci., August 1, 2006; 92(2): 545 - 559.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
C. Persson, D. Subramaniyam, T. Stevens, and S. Janciauskiene
Do Native and Polymeric α1-Antitrypsin Activate Human Neutrophils In Vitro?
Chest, June 1, 2006; 129(6): 1683 - 1692.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
I. Petrache, I. Fijalkowska, L. Zhen, T. R. Medler, E. Brown, P. Cruz, K.-H. Choe, L. Taraseviciene-Stewart, R. Scerbavicius, L. Shapiro, et al.
A Novel Antiapoptotic Role for {alpha}1-Antitrypsin in the Prevention of Pulmonary Emphysema
Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1222 - 1228.
[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
A. Churg, R. D. Wang, H. Tai, X. Wang, C. Xie, and J. L. Wright
Tumor Necrosis Factor-{alpha} Drives 70% of Cigarette Smoke-induced Emphysema in the Mouse
Am. J. Respir. Crit. Care Med., September 1, 2004; 170(5): 492 - 498.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. L. Keith, Y. E. Miller, T. M. Hudish, C. E. Girod, S. Sotto-Santiago, W. A. Franklin, R. A. Nemenoff, T. H. March, S. P. Nana-Sinkam, and M. W. Geraci
Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice
Cancer Res., August 15, 2004; 64(16): 5897 - 5904.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 301 - 313.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
R. A. Stockley
"Knock-out" Mouse: Down But Not Out
Am. J. Respir. Crit. Care Med., July 15, 2003; 168(2): 145 - 146.
[Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2003 American Thoracic Society 		  Portfolio of grants