title: A Comparative Study of Lung Host Defense in Murine Obesity Models. Insights into Neutrophil Function.
abstract: We have shown that obesity-associated attenuation of murine acute lung injury is driven, in part, by blunted neutrophil chemotaxis, yet differences were noted between the two models of obesity studied. We hypothesized that obesity-associated impairment of multiple neutrophil functions contributes to increased risk for respiratory infection but that such impairments may vary between murine models of obesity. We examined the most commonly used murine obesity models (diet-induced obesity, db/db, CPE(fat/fat), and ob/ob) using a Klebsiella pneumoniae pneumonia model and LPS-induced pneumonitis. Marrow-derived neutrophils from uninjured lean and obese mice were examined for in vitro functional responses. All obesity models showed impaired clearance of K. pneumoniae, but in differing temporal patterns. Failure to contain infection in obese mice was seen in the db/db model at both 24 and 48 hours, yet this defect was only evident at 24 hours in CPE(fat/fat) and ob/ob models, and at 48 hours in diet-induced obesity. LPS-induced airspace neutrophilia was decreased in all models, and associated with blood neutropenia in the ob/ob model but with leukocytosis in the others. Obese mouse neutrophils from all models demonstrated impaired chemotaxis, whereas neutrophil granulocyte colony-stimulating factor-mediated survival, LPS-induced cytokine transcription, and mitogen-activated protein kinase and signal transducer and activator of transcription 3 activation in response to LPS and granulocyte colony-stimulating factor, respectively, were variably impaired across the four models. Obesity-associated impairment of host response to lung infection is characterized by defects in neutrophil recruitment and survival. However, critical differences exist between commonly used mouse models of obesity and may reflect variable penetrance of elements of the metabolic syndrome, as well as other factors.
authors.affiliation: 1 Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands; and.|Departments of 2 Medicine and.
authors.forename: Niki D J
authors.initials: ND
authors.lastname: Ubags
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Elianne
authors.initials: E
authors.lastname: Burg
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Maryellen
authors.initials: M
authors.lastname: Antkowiak
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Wallace
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Estee
authors.initials: E
authors.lastname: Dilli
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Jenna
authors.initials: J
authors.lastname: Bement
authors.affiliation: 3 Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wargo
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.affiliation: 1 Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands; and.
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Suratt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000150:complications / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D011014:Pneumonia / Q000150:complications / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein; D008070:Lipopolysaccharides; D016179:Granulocyte Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases
keywords: acute respiratory distress syndrome; innate immunity; neutrophil; obesity; pneumonia