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Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2016 Feb; Vol. 54 (2), pp. 210-21. - Publication Year :
- 2016
-
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.
- Subjects :
- Animals
Animals, Newborn
Cytokines immunology
Cytokines metabolism
Diphtheria Toxin genetics
Diphtheria Toxin metabolism
Disease Models, Animal
Epithelial Sodium Channels genetics
Epithelial Sodium Channels metabolism
Genetic Predisposition to Disease
Inflammation Mediators immunology
Inflammation Mediators metabolism
Luminescent Proteins genetics
Luminescent Proteins metabolism
Lung metabolism
Lung microbiology
Macrophages metabolism
Mice, Inbred C57BL
Mice, Transgenic
Muramidase genetics
Pasteurella Infections genetics
Pasteurella Infections metabolism
Pasteurella Infections microbiology
Pasteurella pneumotropica pathogenicity
Peptide Fragments genetics
Peptide Fragments metabolism
Phenotype
Pneumonia, Bacterial genetics
Pneumonia, Bacterial metabolism
Pneumonia, Bacterial microbiology
Promoter Regions, Genetic
Lung immunology
Macrophages immunology
Mucociliary Clearance
Pasteurella Infections immunology
Pasteurella pneumotropica immunology
Pneumonia, Bacterial immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 54
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 26121027
- Full Text :
- https://doi.org/10.1165/rcmb.2014-0111OC