Signaling pathways regulating the airway phenotype of mice exhibiting airway surface dehydration

Abstract

Overexpression of the epithelial Na+ channel βsubunit (gene Scnn1b) in mouse airways results in airway surface dehydration, neonatal mortality, mucous cell metaplasia and airway inflammation. Crossbreeding Scnn1b‐Tg mice with gene‐deficient mice enables quick and efficient determination of specific pathways relevant to the development of lung pathology. We bred Scnn1b‐Tg mice with mice deficient in: 1) IL‐4 receptor alpha chain (IL‐4Rα), shared by IL‐4 and IL‐13 receptors; 2) TNFα; 3) TNFα receptor 1 (TNFαR1), and evaluated inflammatory infiltrate, cytokine profile, lung pathology, and airway bioelectrics. In Scnn1b‐Tg mice, absence of IL‐4Rα improved neonatal survival and was associated with decreased mucous cells and eosinophilic infiltrate at day 10. However, absence of IL‐4Rα did not affect the chronic inflammatory infiltrate and lung pathology in adult Scnn1b‐Tg mice. Although TNFα was increased in Scnn1b airways, absence of TNFα or TNFαR1 did not ameliorate the lung phenotype of Scnn1b‐Tg mice nor modify airways bioelectrics. To assess the contribution of IL‐1β and TLR pathways, we are currently breeding the Scnn1b‐Tg mice with mice deficient in the adaptor molecule MyD88. These results indicate that multiple pathways contribute to airway inflammation and remodeling in the setting of surface dehydration and mucus stasis.Funded by CFF grants LIVRAG04I0 and RANDEL07P0, and NIH P50 HL060280 to R.C.B