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

作者：Saini Yogesh^*; Wilkinson Kristen J; Terrell Kristy A; Burns Kimberlie A; Livraghi Butrico Alessandra; Doerschuk Claire M; O'Neal Wanda K; Boucher Richard C

来源：American Journal of Respiratory Cell and Molecular Biology, 2016, 54(2): 210-221.

DOI：10.1165/rcmb.2014-0111OC

• alveolar macrophages
• macrophage depletion
• sodium channel beta subunit transgenic mice
• airway mucus obstruction
• airway inflammation

Resident immune cells (e.g., macrophages [M Phi Phi s]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary M Phi function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter-mediated M Phi depletion was generated, characterized, and crossed with the sodium channel beta subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A-mediated depletion of LysM(+) pulmonary M Phi s 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(+) M Phi depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM(+) M Phi-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(+) M Phi-depleted Scnn1b-Tg mice. However, the nonpneumonic LysM(+) M Phi-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 M Phi-mucus clearance interactions with respect to both infectious and inflammatory components of muco-obstructive lung disease.

• 出版日期2016-2