title: Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation.
abstract: It has been postulated that mucus stasis is central to the pathogenesis of obstructive lung diseases. In Scnn1b-transgenic (Scnn1b-Tg⁺ mice, airway-targeted overexpression of the epithelial Na⁺ channel β subunit causes airway surface dehydration, which results in mucus stasis and inflammation. Bronchoalveolar lavage from neonatal Scnn1b-Tg⁺ mice, but not wild-type littermates, contained increased mucus, bacteria, and neutrophils, which declined with age. Scnn1b-Tg⁺ mice lung bacterial flora included environmental and oropharyngeal species, suggesting inhalation and/or aspiration as routes of entry. Genetic deletion of the Toll-interleukin-1 receptor adapter molecule MyD88 in Scnn1b-Tg⁺ mice did not modify airway mucus obstruction, but caused defective neutrophil recruitment and increased bacterial infection, which persisted into adulthood. Scnn1b-Tg⁺ mice derived into germ-free conditions exhibited mucus obstruction similar to conventional Scnn1b-Tg⁺ mice and sterile inflammation. Collectively, these data suggest that dehydration-induced mucus stasis promotes infection, compounds defects in other immune mechanisms, and alone is sufficient to trigger airway inflammation.
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. alessandra_livraghi@med.unc.edu
authors.forename: A
authors.initials: A
authors.lastname: Livraghi-Butrico
authors.forename: E J
authors.initials: EJ
authors.lastname: Kelly
authors.forename: E R
authors.initials: ER
authors.lastname: Klem
authors.forename: H
authors.initials: H
authors.lastname: Dang
authors.forename: M C
authors.initials: MC
authors.lastname: Wolfgang
authors.forename: R C
authors.initials: RC
authors.lastname: Boucher
authors.forename: S H
authors.initials: SH
authors.lastname: Randell
authors.forename: W K
authors.initials: WK
authors.lastname: O'Neal
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction
chemical_list: D053503:Epithelial Sodium Channels; D053594:Myeloid Differentiation Factor 88; C507049:Scnn1b protein, mouse