Abstract
Herein, we tested the hypothesis low molecular weight hyaluronan (LMW-HA) inhibits lung epithelial ion transport in-vivo, ex-vivo, and in-vitro by activating the calcium-sensing receptor (CaSR). Intranasal instillation of LMW-HA (150μg/ml) to C57BL/6 mice inhibited their alveolar fluid clearance (AFC) by 75%, increased the epithelial lining fluid (ELF) thickness threefold, and lung wet/dry (W/D) ratio by 20% 24hrs later. Incubation of lung slices from mouse and human lungs with 150μg/ml LMW-HA decreased the open probability (Po) of ENaC in ATII cell by more than 50% in 4hrs, inhibited amiloride sensitive short circuit current (SCC) 4hrs post exposure, and Cl− current through CFTR by more than 70%, and Na,K-ATPase current by 66% at 24hrs. In all cases the inhibitory effect of LMW-HA on lung epithelial ion transport in vivo, ex vivo, and in vitro preparations were reversed by the administration of 1μM of NPS2143, a CaSR inhibitor, or 150μg/ml HMW-HA. In HEK-293 cells co-transfected with CaSR and the calcium sensitive Cl− channel TMEM16-A, LMW-HA activated an inward Cl− current. These data are the first demonstration of the inhibitory effects of LMW-HA on lung epithelial ion and water transport, and are due to the activation of CaSR and its downstream signaling cascades.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest statement: The authors have declared that no conflict of interest exists.
