Fusion Dependent Activation of Vesicular P2X4 Receptors Leads to a Volume Increase in Alveolar Type II Epithelial Cells - Coupling Secretion and Lung Fluid Homeostasis?

Abstract

Regulated fluid transport in the lung is a necessity for maintenance of a healthy lung environment. However, the role of the alveolar epithelium, consisting of alveolar type I and II (ATII) cells, remains largely undetermined. While the ATII cell is mainly known for secretion of lung surfactant via exocytosis of lamellar bodies (LBs), it is also thought that it may assist in fluid homeostasis as well, both critical for alveolar function. Directed ion transport across the ATII cell will result in secretion or absorption of fluid into or from the alveolar hypophase, respectively. We have recently described that exocytic fusion of LBs with the plasma membrane (PM) results in a transient, non-selective, inward-rectifying, cation current across P2X4 purinergic receptors located on the membranes of fused LBs (PNAS 2011, 108(35):14503-8). This leads us to propose that regulation of LB exocytosis also modulates fluid transport across the alveolar epithelium via this “fusion-activated” cation influx. Experiments combining fluorescence and atomic force microscopy (AFM) confirmed that exocytosis of LBs leads to an instant increase in ATII cell volume that is regulated within mins. Following stimulation of ATII cells with ATP, the height of the ATII cells increased by 30% in cells when LBs fused with the PM after stimulation, but slightly decreased in cell without fusing LBs. These data indicate a link between LB fusion (and hence surfactant secretion) and regulation of fluid transport.