title: Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses.
abstract: Resident immune cells (e.g., macrophages [MΦs]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary MΦ function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter-mediated MΦ depletion was generated, characterized, and crossed with the sodium channel β subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A-mediated depletion of LysM(+) pulmonary MΦs in wild-type mice with normal mucus clearance resulted in lethal pneumonia in 24% of neonates. The pneumonias were dominated by Pasteurella pneumotropica and accompanied by emaciation, neutrophilic inflammation, and elevated Th1 cytokines. The incidence of emaciation and pneumonia reached 51% when LysM(+) MΦ depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM(+) MΦ-depleted Scnn1b-Tg mice, pneumonias were associated with a broader spectrum of bacterial species and a significant reduction in airway mucus plugging. Bacterial burden (CFUs) was comparable between Scnn1b-Tg and nonpneumonic LysM(+) MΦ-depleted Scnn1b-Tg mice. However, the nonpneumonic LysM(+) MΦ-depleted Scnn1b-Tg mice exhibited increased airway inflammation, the presence of neutrophilic infiltration, and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid compared with Scnn1b-Tg mice. Collectively, these data identify key MΦ-mucus clearance interactions with respect to both infectious and inflammatory components of muco-obstructive lung disease.
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.|2 Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Saini
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Wilkinson
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Terrell
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Kimberlie A
authors.initials: KA
authors.lastname: Burns
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Livraghi-Butrico
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Doerschuk
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Wanda K
authors.initials: WK
authors.lastname: O'Neal
authors.affiliation: 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004167:Diphtheria Toxin / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009079:Mucociliary Clearance; D009113:Muramidase / Q000235:genetics; D010326:Pasteurella Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D044142:Pasteurella pneumotropica / Q000276:immunology* / Q000472:pathogenicity; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D011401:Promoter Regions, Genetic
chemical_list: D016207:Cytokines; D004167:Diphtheria Toxin; D053503:Epithelial Sodium Channels; D018836:Inflammation Mediators; D008164:Luminescent Proteins; D010446:Peptide Fragments; C029795:diphtheria toxin fragment A; D009113:Muramidase
keywords: airway inflammation; airway mucus obstruction; alveolar macrophages; macrophage depletion; sodium channel β subunit transgenic mice