| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Anesthesiology and Intensive Care Medicine and
Department of Pathology, Tübingen University Hospital, Tübingen, Germany;
Department of Anesthesia, Perioperative and Pain Medicine, Children’s Hospital, Harvard Medical School, Boston, MA 02115; and
Institute of Brain Research, Tübingen University Hospital, Tübingen, Germany
Acute lung injury (ALI), such as that which occurs with mechanical ventilation, contributes to morbidity and mortality of critical illness. Nonetheless, in many instances, ALI resolves spontaneously through unknown mechanisms. Therefore, we hypothesized the presence of innate adaptive pathways to protect the lungs during mechanical ventilation. In this study, we used ventilator-induced lung injury as a model to identify endogenous mechanisms of lung protection. Initial in vitro studies revealed that supernatants from stretch-induced injury contained a stable factor which diminished endothelial leakage. This factor was subsequently identified as adenosine. Additional studies in vivo revealed prominent increases in pulmonary adenosine levels with mechanical ventilation. Because ectoapyrase (CD39) and ecto-5'-nucleotidase (CD73) are rate limiting for extracellular adenosine generation, we examined their contribution to ALI. In fact, both pulmonary CD39 and CD73 are induced by mechanical ventilation. Moreover, we observed pressure- and time-dependent increases in pulmonary edema and inflammation in ventilated cd39–/– mice. Similarly, pharmacological inhibition or targeted gene deletion of cd73 was associated with increased symptom severity of ventilator-induced ALI. Reconstitution of cd39–/– or cd73–/– mice with soluble apyrase or 5'-nucleotidase, respectively, reversed such increases. In addition, ALI was significantly attenuated and survival improved after i.p. treatment of wild-type mice with soluble apyrase or 5'-nucleotidase. Taken together, these data reveal a previously unrecognized role for CD39 and CD73 in lung protection and suggest treatment with their soluble compounds as a therapeutic strategy for noninfectious ALI.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Fortune Grant 1416-0-0, Interdisziplinäres Zentrum für Klinische Forschung Verbundprojekt 1597-0-0, and Deutsche Forschungsgemeinschaft Grant EL274/2-2 (to H.K.E.) and Interdiziplinäres Zentrum für Klinisehe Forschung Nachwuchsgruppe 1605-0-0 (to T.E.).
2 Address correspondence and reprint requests to Dr. Holger K. Eltzschig, Department of Anesthesiology and Intensive Care Medicine, Center for Biomedical Research, Tübingen University Hospital, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany. E-mail address: heltzschig{at}partners.org
3 Abbreviations used in this paper: ALI, acute lung injury; HMEC, human microvascular endothelial cell; BAL, bronchoalveolar lavage; 8-PT, 8-phenyl-theophylline; APCP, adenosine 5'-(
,
-methylene) diphosphate; AR, adenosine receptor; PMN, polymorphonuclear neutrophil; ADA, adenosine deaminase; MPO, myeloperoxidase; PaO2, arterial partial pressure of oxygen; mbar, millibar.
This article has been cited by other articles:
|
|
 |
|
  M. L. Hart, M. Henn, D. Kohler, D. Kloor, M. Mittelbronn, I. C. Gorzolla, G. L. Stahl, and H. K. Eltzschig Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia-reperfusion injury FASEB J, August 1, 2008; 22(8): 2784 - 2797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Hart, D. Kohler, T. Eckle, D. Kloor, G. L. Stahl, and H. K. Eltzschig Direct Treatment of Mouse or Human Blood With Soluble 5'-Nucleotidase Inhibits Platelet Aggregation Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1477 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mikhailov, A. Sokolovskaya, G. G. Yegutkin, H. Amdahl, A. West, H. Yagita, R. Lahesmaa, L. F. Thompson, S. Jalkanen, D. Blokhin, et al. CD73 Participates in Cellular Multiresistance Program and Protects against TRAIL-Induced Apoptosis J. Immunol., July 1, 2008; 181(1): 464 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Fowler, N. K. J. Adhikari, D. C. Scales, W. L. Lee, and G. D. Rubenfeld Update in Critical Care 2007 Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 808 - 819. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Martinon Detection of immune danger signals by NALP3 J. Leukoc. Biol., March 1, 2008; 83(3): 507 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Eckle, M. Faigle, A. Grenz, S. Laucher, L. F. Thompson, and H. K. Eltzschig A2B adenosine receptor dampens hypoxia-induced vascular leak Blood, February 15, 2008; 111(4): 2024 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jalkanen and M. Salmi VAP-1 and CD73, Endothelial Cell Surface Enzymes in Leukocyte Extravasation Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 18 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kohler, T. Eckle, M. Faigle, A. Grenz, M. Mittelbronn, S. Laucher, M. L. Hart, S. C. Robson, C. E. Muller, and H. K. Eltzschig CD39/Ectonucleoside Triphosphate Diphosphohydrolase 1 Provides Myocardial Protection During Cardiac Ischemia/Reperfusion Injury Circulation, October 16, 2007; 116(16): 1784 - 1794. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
