Published ahead of print on October 6, 2005, doi:10.1164/rccm.200506-909OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 2, January 2006, 212-218
A more recent version of this article appeared on January 15, 2006
Submitted on June 13, 2005
Accepted on October 3, 2005
Leptin Corrects Host Defense Defects Following Acute Starvation in Murine Pneumococcal Pneumonia
Peter Mancuso1*, Gary B Huffnagle2, Mihal A Olszewski3, John Phipps1, and Marc Peters-Golden4
1 Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA,
2 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA,
3 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; VA Medical Center, Ann Arbor, Michigan, USA,
4 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
* To whom correspondence should be addressed. E-mail: pmancuso{at}umich.edu.
Rationale: Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia. Objectives: To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice. Methods: C57BL/6 mice were either fed ad libidum or fasted for 48h and given an intraperitoneal injection of saline or recombinant leptin (1µg/g of body weight) twice daily for 48 h prior to bacterial challenge. Mice were challenged with 105 CFUs of S. pneumoniae via the intranasal route. Measurements and Main Results: Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts, IL-6, and MIP-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium ionophore-stimulated leukotriene B4 synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, and alveolar macrophage bacterial killing and leukotriene B4 synthesis. Conclusions: These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically.
Key words: pneumonia, Streptococcus pneumoniae, malnutrition, leptin
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