This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200603-312OCv1 175/6/587    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bellmeyer, A. Articles by Mutlu, G. M. Search for Related Content PubMed PubMed Citation Articles by Bellmeyer, A. Articles by Mutlu, G. M.

Leptin Resistance Protects Mice from Hyperoxia-induced Acute Lung Injury

¹ Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Gökhan M. Mutlu, M.D., Northwestern University Feinberg School of Medicine, 240 East Huron Street, McGaw M-300, Chicago, IL 60611. E-mail: g-mutlu{at}northwestern.edu

Rationale: Human data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown.

Objectives: To determine whether leptin resistance, which is seen in humans with diabetes, protects mice from hyperoxic lung injury.

Methods: Wild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O₂) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo.

Measurements and Main Results: Lung leptin levels were increased both in wild-type and leptin receptor–defective db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared with wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared with wild-type control animals, db/db mice were resistant to hyperoxia-induced mortality (lethal dose for 50% of mice, 152 vs. 108 h). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of proinflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na,K-ATPase function compared with wild-type mice.

Conclusions: These results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.

Key Words: alveolar fluid clearance • pulmonary edema • Na,K-ATPase • diabetes mellitus • oxygen

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Human data suggest that patients with diabetes mellitus are less likely to develop acute lung injury/acute respiratory distress syndrome (ALI/ARDS); however, the mechanism by which diabetes mellitus confers this protection is unknown. What This Study Adds to the Field Leptin may play a role in the pathogenesis of ALI/ARDS and resistance to its effects may attenuate ALI/ARDS.

 

This article has been cited by other articles:

				J. H. J. Vernooy, K. R. Bracke, N. E. A. Drummen, N. S. A. Pauwels, L. Zabeau, R. J. van Suylen, J. Tavernier, G. F. Joos, E. F. M. Wouters, and G. G. Brusselle Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice J. Immunol., June 15, 2010; 184(12): 7169 - 7177. [Abstract] [Full Text] [PDF]

				A. P. Comellas, A. M. Kelly, H. E. Trejo, A. Briva, J. Lee, J. I. Sznajder, and L. A. Dada Insulin regulates alveolar epithelial function by inducing Na+/K+-ATPase translocation to the plasma membrane in a process mediated by the action of Akt J. Cell Sci., April 15, 2010; 123(8): 1343 - 1351. [Abstract] [Full Text] [PDF]

				P. Mancuso Obesity and lung inflammation J Appl Physiol, March 1, 2010; 108(3): 722 - 728. [Abstract] [Full Text] [PDF]

				M N Gong, E K Bajwa, B T Thompson, and D C Christiani Body mass index is associated with the development of acute respiratory distress syndrome Thorax, January 1, 2010; 65(1): 44 - 50. [Abstract] [Full Text] [PDF]

				S. A. Shore, J. E. Lang, D. I. Kasahara, F. L. Lu, N. G. Verbout, H. Si, E. S. Williams, R. D. Terry, A. Lee, and R. A. Johnston Pulmonary responses to subacute ozone exposure in obese vs. lean mice J Appl Physiol, November 1, 2009; 107(5): 1445 - 1452. [Abstract] [Full Text] [PDF]

				J H J Vernooy, N E A Drummen, R J van Suylen, R H E Cloots, G M Moller, K R Bracke, S Zuyderduyn, M A Dentener, G G Brusselle, P S Hiemstra, et al. Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers Thorax, January 1, 2009; 64(1): 26 - 32. [Abstract] [Full Text] [PDF]

				G. Matute-Bello, C. W. Frevert, and T. R. Martin Animal models of acute lung injury Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L379 - L399. [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]

				R. A. Johnston, M. Zhu, Y. M. Rivera-Sanchez, F. L. Lu, T. A. Theman, L. Flynt, and S. A. Shore Allergic Airway Responses in Obese Mice Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 650 - 658. [Abstract] [Full Text] [PDF]

				G. M. Mutlu, D. Machado-Aranda, J. E. Norton, A. Bellmeyer, D. Urich, R. Zhou, and D. A. Dean Electroporation-mediated Gene Transfer of the Na+,K+-ATPase Rescues Endotoxin-induced Lung Injury Am. J. Respir. Crit. Care Med., September 15, 2007; 176(6): 582 - 590. [Abstract] [Full Text] [PDF]