LPS decreases CFTR open probability and mucociliary transport through generation of reactive oxygen species

• DOI: 10.1016/j.redox.2021.101998
• Publication Date: 2021-04-30T17:06:49Z
• Authors: Do Yeon Cho; Shaoyan Zhang; Ahmed Lazrak; Daniel Skinner; Harrison M. Thompson; Jessica Grayson; Purushotham Guroji; Saurabh Aggarwal; Zsuzsanna Bebok; Steven M. Rowe; Sadis Matalon; Eric J. Sorscher; Bradford A. Woodw...
• Keywords: Mucociliary clearance; Mitochondrial ROS

Lipopolysaccharide (LPS) serves as the interface between gram-negative bacteria (GNB) and innate immune response in respiratory epithelial cells (REC). Herein, we describe a novel biological role of LPS that permits GNB to persist tract through inducing CFTR mucociliary dysfunction. reduced cystic fibrosis transmembrane conductance regulater (CFTR)-mediated short-circuit current mammalian REC Ussing chambers nearly abrogated single channel activity (defined forskolin-activated Cl- currents) patch clamp studies, effects which were blocked with toll-like receptor (TLR)-4 inhibitor. Unitary single-channel amplitude unaffected, but open probability number active channels markedly decreased. increased cytoplasmic mitochondrial reactive oxygen species resulting carbonylation. All exposure eliminated when glutathione was added medium along LPS. Functional microanatomy parameters, including transport, human sinonasal vitro also decreased, restored co-incubation or TLR-4 In vivo measurements, following application nasal cavities showed significant decreases transepithelial secretion measured by potential difference (NPD) – an effect nullified These data provide definitive evidence LPS-generated intermediates downregulate function results fibrosis-type disease. Findings have implications for therapeutic approaches intent on stimulating and/or reducing oxidative stress decrease sequelae airway colonization infection.