| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109
Plasminogen activator inhibitor-1 (PAI-1)-deficient transgenic mice have improved survival and less fibrosis after intratracheal bleomycin instillation. We hypothesize that PAI-1 deficiency limits scarring through unopposed plasminogen activation. If this is indeed true, then we would expect increased urokinase-type plasminogen activator (uPA) expression to result in a similar reduction in scarring and improvement in mortality. To test our hypothesis, using the tetracycline gene regulatory system, we have generated a transgenic mouse model with the features of inducible, lung-specific uPA production. After doxycycline administration, these transgenic animals expressed increased levels of uPA in their bronchoalveolar lavage (BAL) fluid that accelerated intrapulmonary fibrin clearance. Importantly, this increased plasminogen activator production led to a reduction in both lung collagen accumulation and mortality after bleomycin-induced injury. These results suggest that PAI-1 deficiency does protect against the effects of bleomycin-induced lung injury through unopposed plasmin generation. By allowing the manipulation of plasminogen activation at different phases of the fibrotic process, this model will serve as a powerful tool in further investigations into the pathogenesis of pulmonary fibrosis.
plasminogen activator; plasmin; bleomycin; tetracycline
This article has been cited by other articles:
|
|
 |
|
  I-M. Wang, S. Stepaniants, Y. Boie, J. R. Mortimer, B. Kennedy, M. Elliott, S. Hayashi, L. Loy, S. Coulter, S. Cervino, et al. Gene Expression Profiling in Patients with Chronic Obstructive Pulmonary Disease and Lung Cancer Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 402 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. B. Moore and C. M. Hogaboam Murine models of pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L152 - L160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Horowitz, D. S. Rogers, R. H. Simon, T. H. Sisson, and V. J. Thannickal Plasminogen Activation Induced Pericellular Fibronectin Proteolysis Promotes Fibroblast Apoptosis Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 78 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Yamaguchi, J. M. Lopez-Guisa, X. Cai, S. J. Collins, D. M. Okamura, and A. A. Eddy Endogenous urokinase lacks antifibrotic activity during progressive renal injury Am J Physiol Renal Physiol, July 1, 2007; 293(1): F12 - F19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsuoka, T. H. Sisson, T. Nishiuma, and R. H. Simon Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 705 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Sisson, J. M. Hansen, M. Shah, K. E. Hanson, M. Du, T. Ling, R. H. Simon, and P. J. Christensen Expression of the Reverse Tetracycline-Transactivator Gene Causes Emphysema-Like Changes in Mice Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 552 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fujita, Q. Ye, H. Ouchi, E. Harada, I. Inoshima, K. Kuwano, and Y. Nakanishi Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice Antimicrob. Agents Chemother., February 1, 2006; 50(2): 739 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Vayalil, M. Olman, J. E. Murphy-Ullrich, E. M. Postlethwait, and R.-M. Liu Glutathione restores collagen degradation in TGF-{beta}-treated fibroblasts by blocking plasminogen activator inhibitor-1 expression and activating plasminogen Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L937 - L945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Koh, S. C. Bryer, A. M. Pucci, and T. H. Sisson Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration Am J Physiol Cell Physiol, July 1, 2005; 289(1): C217 - C223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Lazar, P. J. Christensen, M. Du, B. Yu, N. M. Subbotina, K. E. Hanson, J. M. Hansen, E. S. White, R. H. Simon, and T. H. Sisson Plasminogen Activator Inhibitor-1 Impairs Alveolar Epithelial Repair by Binding to Vitronectin Am. J. Respir. Cell Mol. Biol., December 1, 2004; 31(6): 672 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Moriwaki, A. Stempien-Otero, M. Kremen, A. E. Cozen, and D. A. Dichek Overexpression of Urokinase by Macrophages or Deficiency of Plasminogen Activator Inhibitor Type 1 Causes Cardiac Fibrosis in Mice Circ. Res., September 17, 2004; 95(6): 637 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hattori, S. Mizuno, Y. Yoshida, K. Chin, M. Mishima, T. H. Sisson, R. H. Simon, T. Nakamura, and M. Miyake The Plasminogen Activation System Reduces Fibrosis in the Lung by a Hepatocyte Growth Factor-Dependent Mechanism Am. J. Pathol., March 1, 2004; 164(3): 1091 - 1098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Idell The Matrix Unloaded: Aerosolized Heparin or Urokinase for Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., December 1, 2003; 168(11): 1268 - 1269. [Full Text] [PDF]
|
|
|
|
|
|
J. D. Savov, D. M. Brass, K. G. Berman, E. McElvania, and D. A. Schwartz Fibrinolysis in LPS-induced chronic airway disease Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L940 - L948. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
