help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on March 2, 2006, doi:10.1164/rccm.200512-1842OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200512-1842OCv1
173/11/1222    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 Petrache, I.
Right arrow Articles by Tuder, R. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Petrache, I.
Right arrow Articles by Tuder, R. M.
American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 1222-1228, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200512-1842OC

Original Article

A Novel Antiapoptotic Role for {alpha}1-Antitrypsin in the Prevention of Pulmonary Emphysema

Irina Petrache, Iwona Fijalkowska, Lijie Zhen, Terry R. Medler, Emile Brown, Pedro Cruz, Kang-Hyeon Choe, Laimute Taraseviciene-Stewart, Robertas Scerbavicius, Lee Shapiro, Bing Zhang, Sihong Song, Dan Hicklin, Norbert F. Voelkel, Terence Flotte and Rubin M. Tuder

Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pediatrics, School of Medicine, and Department of Pharmaceutics, College of Pharmacy, University of Florida at Gainesville, Gainesville, Florida; Division of Pulmonary Sciences and Critical Care Medicine, Pulmonary Hypertension Center, and Division of Infectious Disease, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and Imclone Systems, Inc., New York, New York

Correspondence and requests for reprints should be addressed to Irina Petrache, M.D., Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indiana University, 1481 West 10th Street, 111P-IU, Indianapolis, IN 46202. E-mail: ipetrach{at}iupui.edu

Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of {alpha}1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke–induced emphysema.

Objectives: We propose that, in addition to its antielastolytic effects, {alpha}1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis.

Methods, Measurements, and Main Results: Transduction of human {alpha}1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human {alpha}1-antitrypsin intravenously.

Conclusions: Our findings suggest that inhibition of structural alveolar cell apoptosis by {alpha}1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of {alpha}1-antitrypsin.

Key Words: antiprotease • caspase • chronic obstructive pulmonary disease • oxidative stress • serpin




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
 Proc Am Thorac SocHome page
C. P. Hersh, D. L. DeMeo, and E. K. Silverman
National Emphysema Treatment Trial State of the Art: Genetics of Emphysema
Proceedings of the ATS, May 1, 2008; 5(4): 486 - 493.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
I Petrache, K Diab, K S Knox, H L Twigg III, R S Stephens, S Flores, and R M Tuder
HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism
Thorax, May 1, 2008; 63(5): 463 - 469.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
G. Borzone, L. Liberona, P. Olmos, C. Saez, M. Meneses, T. Reyes, R. Moreno, and C. Lisboa
Rat and hamster species differences in susceptibility to elastase-induced pulmonary emphysema relate to differences in elastase inhibitory capacity
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1342 - R1349.
[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
 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
K. F. Rabe, B. Beghe, F. Luppi, and L. M. Fabbri
Update in Chronic Obstructive Pulmonary Disease 2006
Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1222 - 1232.
[Full Text] [PDF]

Home page
 DiabetesHome page
B. Zhang, Y. Lu, M. Campbell-Thompson, T. Spencer, C. Wasserfall, M. Atkinson, and S. Song
{alpha}1-Antitrypsin Protects {beta}-Cells From Apoptosis
Diabetes, May 1, 2007; 56(5): 1316 - 1323.
[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
 Proc Am Thorac SocHome page
R. M. Tuder, T. Yoshida, I. Fijalkowka, S. Biswal, and I. Petrache
Role of Lung Maintenance Program in the Heterogeneity of Lung Destruction in Emphysema
Proceedings of the ATS, November 1, 2006; 3(8): 673 - 679.
[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
 Proc Am Thorac SocHome page
R. M. Tuder, T. Yoshida, W. Arap, R. Pasqualini, and I. Petrache
State of the Art. Cellular and Molecular Mechanisms of Alveolar Destruction in Emphysema: An Evolutionary Perspective
Proceedings of the ATS, August 1, 2006; 3(6): 503 - 510.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2006 American Thoracic Society