Link: http://www.ncbi.nlm.nih.gov/pubmed/25934671

Am J Physiol Lung Cell Mol Physiol. 2015 May 1:ajplung.00299.2014. doi: 10.1152/ajplung.00299.2014. [Epub ahead of print]

Defective Parasympathetic Innervation is Associated with Airway Branching Abnormalities in Experimental CDH.
Rhodes J1, Saxena D2, Zhang G3, Gittes GK4, Potoka DA5.
Author information

Abstract
Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in both the human disease and rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities, and therefore lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to perform E11.5 lung explant cultures with or without the cholinergic agonist carbachol. Airway branching and contractions were quantified. A subset of experiments was performed with the addition of verapamil to inhibit airway contractions. Sox9 immunostaining and BrdU incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. The in vivo effect of carbachol was determined by performing amniotic injections of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared to controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which was decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs, but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH.

Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.

KEYWORDS:
Congenital Diaphragmatic Hernia; Lung Development; Nitrofen Model
PMID: 25934671 [PubMed - as supplied by publisher]