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Departments of
* Environmental Health Sciences,
Pulmonary and Critical Care Medicine, and
Pathology, University of Michigan, Ann Arbor, MI 48109
Leptin is an adipocyte-derived hormone that is secreted in
correlation with total body lipid stores. Serum leptin levels are
lowered by the loss of body fat mass that would accompany starvation
and malnutrition. Recently, leptin has been shown to modulate innate
immune responses such as macrophage phagocytosis and cytokine synthesis
in vitro. To determine whether leptin plays a role in the innate host
response against Gram-negative pneumonia in vivo, we compared the
responses of leptin-deficient and wild-type mice following an
intratracheal challenge of Klebsiella pneumoniae.
Following K. pneumoniae administration, we observed
increased leptin levels in serum, bronchoalveolar lavage fluid, and
whole lung homogenates. In a survival study, leptin-deficient mice, as
compared with wild-type mice, exhibited increased mortality following
K. pneumoniae administration. The increased
susceptibility to K. pneumoniae in the
leptin-deficient mice was associated with reduced bacterial clearance
and defective alveolar macrophage phagocytosis in vitro. The exogenous
addition of very high levels of leptin (500 ng/ml) restored the defect
in alveolar macrophage phagocytosis of K. pneumoniae in
vitro. While there were no differences between wild-type and
leptin-deficient mice in lung homogenate cytokines TNF-
, IL-12, or
macrophage-inflammatory protein-2 after K. pneumoniae
administration, leukotriene synthesis in lung macrophages from
leptin-deficient mice was reduced. Leukotriene production was restored
by the addition of exogenous leptin (500 ng/ml) to macrophages in
vitro. This study demonstrates for the first time that leptin-deficient
mice display impaired host defense in bacterial pneumonia that may be
due to a defect in alveolar macrophage phagocytosis and leukotriene
synthesis.
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