The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury.
OBJECTIVE
One of the hallmarks of severe pneumonia and associated acute lung injury is neutrophil recruitment to the lung. Leptin is thought to be up-regulated in the lung following injury and to exert diverse effects on leukocytes, influencing both chemotaxis and survival. We hypothesized that pulmonary leptin contributes directly to the development of pulmonary neutrophilia during pneumonia and acute lung injury.


METHODS
Controlled human and murine in vivo and ex vivo experimental studies.


METHODS
Research laboratory of a university hospital.


METHODS
Healthy human volunteers and subjects hospitalized with bacterial and H1N1 pneumonia. C57Bl/6 and db/db mice were also used.


METHODS
Lung samples from patients and mice with either bacterial or H1N1 pneumonia and associated acute lung injury were immunostained for leptin. Human bronchoalveolar lavage samples obtained after lipopolysaccharide-induced lung injury were assayed for leptin. C57Bl/6 mice were examined after oropharyngeal aspiration of recombinant leptin alone or in combination with Escherichia coli- or Klebsiella pneumoniae-induced pneumonia. Leptin-resistant (db/db) mice were also examined using the E. coli model. Bronchoalveolar lavage neutrophilia and cytokine levels were measured. Leptin-induced chemotaxis was examined in human blood- and murine marrow-derived neutrophils in vitro.


RESULTS
Injured human and murine lung tissue showed leptin induction compared to normal lung, as did human bronchoalveolar lavage following lipopolysaccharide instillation. Bronchoalveolar lavage neutrophilia in uninjured and infected mice was increased and lung bacterial load decreased by airway leptin administration, whereas bronchoalveolar lavage neutrophilia in infected leptin-resistant mice was decreased. In sterile lung injury by lipopolysaccharide, leptin also appeared to decrease airspace neutrophil apoptosis. Both human and murine neutrophils migrated toward leptin in vitro, and this required intact signaling through the Janus Kinase 2/phosphatidylinositol-4,5-bisphosphate 3-kinase pathway.


CONCLUSIONS
We demonstrate that pulmonary leptin is induced in injured human and murine lungs and that this cytokine is effective in driving alveolar airspace neutrophilia. This action appears to be caused by direct effects of leptin on neutrophils.
1Department of Medicine, University of Vermont College of Medicine, Burlington, VT. 2Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands. 3Department of Medical Protein Research, Ghent University, Ghent, Belgium. 4Department of Medicine, National Jewish Health, Denver, CO. 5Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico. 6Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT. 7Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA.
Niki D
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Ubags
Juanita H
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Vernooy
Elianne
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Burg
Catherine
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Hayes
Jenna
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Bement
Estee
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Dilli
Lennart
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Zabeau
Edward
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Abraham
Katie R
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Poch
Jerry A
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Nick
Oliver
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Dienz
Joaquin
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Zuñiga
Matthew J
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Wargo
Joseph P
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Mizgerd
Jan
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Tavernier
Mercedes
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Rincón
Matthew E
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Poynter
Emiel F M
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Wouters
Benjamin T
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Suratt
D055371:Acute Lung Injury / Q000209:etiology*; D000818:Animals; D005260:Female; D006801:Humans; D020738:Leptin / Q000502:physiology*; D007960:Leukocyte Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils; D018410:Pneumonia, Bacterial / Q000209:etiology*; D011024:Pneumonia, Viral / Q000209:etiology*
D020738:Leptin