Low molecular weight hyaluronan inhibits lung epithelial ion channels by activating the calcium-sensing receptor

Ahmed Lazrak; Weifeng Song; Zhihong Yu; Shaoyan Zhang; Anoma Nellore; Charles W Hoopes; Bradford A Woodworth; Sadis Matalon

doi:10.1016/j.matbio.2023.02.002

Low molecular weight hyaluronan inhibits lung epithelial ion channels by activating the calcium-sensing receptor

Matrix Biol. 2023 Feb:116:67-84. doi: 10.1016/j.matbio.2023.02.002. Epub 2023 Feb 8.

Authors

Ahmed Lazrak¹, Weifeng Song², Zhihong Yu³, Shaoyan Zhang⁴, Anoma Nellore⁵, Charles W Hoopes⁶, Bradford A Woodworth⁴, Sadis Matalon³

Affiliations

¹ Department of Anesthesiology and Perioperative Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA; Division of Molecular and Translational Biomedicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA; Pulmonary Injury and Repair Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA; Gregory Fleming James Cystic Fibrosis Research Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA. Electronic address: ahmedlazrak@uabmc.edu.
² Department of Anesthesiology and Perioperative Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA; Division of Molecular and Translational Biomedicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA.
³ Department of Anesthesiology and Perioperative Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA; Division of Molecular and Translational Biomedicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA; Pulmonary Injury and Repair Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA.
⁴ Department of Otolaryngology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA; Gregory Fleming James Cystic Fibrosis Research Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA.
⁵ Department of Medicine, Division of Infectious Diseases, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35295, USA.
⁶ Division of Cardiothoracic Surgery, Heersink School of Medicine, University of Alabama at Birmingham, AL 35295, USA.

Abstract

Herein, we tested the hypothesis that low molecular weight hyaluronan (LMW-HA) inhibits lung epithelial ions transport in-vivo, ex-vivo, and in-vitro by activating the calcium-sensing receptor (CaSR). Twenty-four hours post intranasal instillation of 50-150 µg/ml LMW-HA to C57BL/6 mice, there was a 75% inhibition of alveolar fluid clearance (AFC), a threefold increase in the epithelial lining fluid (ELF) depth, and a 20% increase in lung wet/dry (W/D) ratio. Incubation of human and mouse precision cut lung slices with 150 µg/ml LMW-HA reduced the activity and the open probability (P_o) of epithelial sodium channel (ENaC) in alveolar epithelial type 2 (ATII) cells, and in mouse tracheal epithelial cells (MTEC) monolayers as early as 4 h. The Cl^- current through cystic fibrosis transmembrane conductance regulator (CFTR) and the activity of Na,K-ATPase were both inhibited by more than 66% at 24 h. The inhibitory effects of LMW-HA on ion channels were reversed by 1 µM NPS-2143, or 150 µg/ml high molecular weight hyaluronan (HMW-HA). In HEK-293 cells expressing the calcium-sensitive Cl^- channel TMEM16-A, CaSR was required for the activation of the Cl^- current by LMW-HA. This is the first demonstration of lung ions and water transport inhibition by LMW-HA, and its mediation through the activation of CaSR.

Keywords: Calcium-sensing receptor; Epithelial ion channels; Hyaluronan; Lung edema; Lung injury.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
HEK293 Cells
Humans
Hyaluronic Acid* / pharmacology
Lung / metabolism
Mice
Mice, Inbred C57BL
Molecular Weight
Receptors, Calcium-Sensing*
Sodium-Potassium-Exchanging ATPase / metabolism
Sodium-Potassium-Exchanging ATPase / pharmacology

Substances

Receptors, Calcium-Sensing
Hyaluronic Acid
Sodium-Potassium-Exchanging ATPase

Abstract

Publication types

MeSH terms

Substances

Grants and funding