TRANSLATIONAL PHYSIOLOGY Peristalsis of airway smooth muscle is developmentally regulated and uncoupled from hypoplastic lung growth

Jesudason, E. C., N. P. Smith, M. G. Connell, D. G. Spiller, M. R. H. White, D. G. Fernig, and P. D. Losty. Peristalsis of airway smooth muscle is developmentally regulated and uncoupled from hypoplastic lung growth. Am J Physiol Lung Cell Mol Physiol 291: L559–L565, 2006. First published April 7, 2006; doi:10.1152/ajplung.00498.2005.—Prenatal airway smooth muscle (ASM) peristalsis appears coupled to lung growth. Moreover, ASM progenitors produce fibroblast growth factor-10 (FGF-10) for lung morphogenesis. Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia, FGF-10 deficiency, and postnatal ASM dysfunction. We hypothesized ASM dysfunction emerges in tandem with, and may contribute toward, the primordial lung hypoplasia that precedes experimental CDH. Spatial origin and frequency of ASM peristaltic waves were measured in normal and hypoplastic rat lungs cultured from day 13.5 of gestation (lung hypoplasia was generated by nitrofen dosing of pregnant dams). Longitudinal lung growth was assayed by bud counts and tracing photomicrographs of cultures. Coupling of lung growth and peristalsis was tested by stimulation studies using serum, FGF-10, or nicotine and inhibition studies with nifedipine or U0126 (MEK1/2 inhibitor). In normal lung, ASM peristalsis is developmentally regulated: proximal ASM becomes quiescent (while retaining capacity for cholinergic-stimulated peristalsis). However, in hypoplastic lung, spontaneous proximal ASM activity persists. FGF-10 corrects this aberrant ASM activity in tandem with improved growth. Stimulation and inhibition studies showed that, unlike normal lung, changes in growth or peristalsis are not consistently accompanied by parallel modulation of the other. ASM peristalsis undergoes FGF-10-regulated spatiotemporal development coupled to lung growth: this process is disrupted early in lung hypoplasia. ASM dysfunction emerges in tandem with and may therefore contribute toward lung hypoplasia in CDH.