Barbara R Grubb

UNCCH, School of Medicine, Medicine

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Airway and lung pathology due to mucosal surface dehydration in β-epithelial Na⁺ channel-overexpressing mice: Role of TNF-α and IL-4Rα signaling, influence of neonatal development, and limited efficacy of glucocorticoid treatment

Alessandra Livraghi; Barbara R. Grubb; Elizabeth J. Hudson; Kristen J. Wilkinson; John K. Sheehan; Marcus A. Mall; Wanda K. O'Neal; Richard C. Boucher; Scott H. Randell (Profiled Authors: Scott H Randell; Barbara R Grubb; Richard C Boucher; Wanda K O'Neal; John K Sheehan)

Journal of Immunology. 2009;182(7):4357-4367.

Overexpression of the epithelial Na⁺ channel β subunit (Scnn1b gene, βENaC protein) in transgenic (Tg) mouse airways dehydrates mucosal surfaces, producing mucus obstruction, inflammation, and neonatal mortality. Airway inflammation includes macrophage activation, neutrophil and eosinophil recruitment, and elevated KC, TNF-α, and chitinase levels. These changes recapitulate aspects of complex human obstructive airway diseases, but their molecular mechanisms are poorly understood. We used genetic and pharmacologic approaches to identify pathways relevant to the development of Scnn1b-Tg mouse lung pathology. Genetic deletion of TNF-α or its receptor, TNFR1, had no measurable effect on the phenotype. Deletion of IL-4Rα abolished transient mucous secretory cell (MuSC) abundance and eosinophilia normally observed in neonatal wild-type mice. Similarly, IL-4Rα deficiency decreased MuSC and eosinophils in neonatal Scnn1b-Tg mice, which correlated with improved neonatal survival. However, chronic lung pathology in adult Scnn1b-Tg mice was not affected by IL-4Rα status. Prednisolone treatment ablated eosinophilia and MuSC in adult Scnn1b-Tg mice, but did not decrease mucus plugging or neutrophilia. These studies demonstrate that: 1) normal neonatal mouse airway development entails an IL-4Rα-dependent, transient abundance of MuSC and eosinophils; 2) absence of IL-4Rα improved neonatal survival of Scnn1b-Tg mice, likely reflecting decreased formation of asphyxiating mucus plugs; and 3) in Scnn1b-Tg mice, neutrophilia, mucus obstruction, and airspace enlargement are IL-4Rα- and TNF-α- independent, and only MuSC and eosinophilia are sensitive to glucocorticoids. Thus, manipulation of multiple pathways will likely be required to treat the complex pathogenesis caused by airway surface dehydration. Copyright © 2009 by The American Association of Immunologists, Inc.

PMID: 19299736     PMCID: PMC2659461

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