Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses

Yogesh Saini, 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.
Kristen J. Wilkinson, 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.
Kristy A. Terrell, 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.
Kimberlie A. Burns, 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.
Alessandra Livraghi-Butrico, 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.
Claire M. Doerschuk, 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.
Wanda K. O'Neal, 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.
Richard C. Boucher, 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.

Document Type

Article

Publication Date

2-1-2016

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.

Publication Source (Journal or Book title)

American journal of respiratory cell and molecular biology

First Page

210

Last Page

21

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