The mesenchymal factors Neuregulin-1β and Leptin modulate alveolar epithelial ion transport

Abstract

The epithelial-mesenchymal relationship has been noted to influence fetal lung development through several pathways, including secretion of fibroblast-pneumocyte factors (FPF) by lung fibroblasts. FPF composition has not been clarified completely, but several factors were proposed to contribute to its paracrine effects. Alveolar epithelial ion transport is crucially involved in both, fetal lung growth and perinatal lung transition. We thus aimed to determine whether two of the proposed FPF components, neuregulin-1β (NRG1) and leptin, modulate epithelial Na+ and Cl- transport in rat fetal distal lung epithelial (FDLE) cells. Epithelial ion transport was measured with Ussing chambers and mRNA expression of ion channels was determined by RT-qPCR. Fibroblast-conditioned media (FCM) was obtained from primary fetal lung fibroblasts. FCM enhanced Na+ transport and cystic fibrosis transmembrane conductance regulator (CFTR) activity in FDLE cells. In addition, epithelial Na+ channel (ENaC) subunit mRNA expression was increased, while CFTR mRNA expression was decreased by FCM. NRG1 increased CFTR activity and CFTR mRNA expression, but reduced Na+ transport and ENaC subunit mRNA expression. In contrast, low leptin concentrations (1 ng/ml) enhanced Na+ transport and ENaC subunit mRNA expression. Leptin concentrations above 1 ng/ml abrogated the stimulatory effect on Na+ transport. The potential FPF components thus both affected alveolar ion transport in different ways by either stimulating CFTR activity or Na+ transport and thereby in conjunction mimicked some effects of FCM on ion transport. NRG1 and leptin might thus be involved in the maturation of alveolar ion channel function.