The role of electrogenic and electroneutral monocarboxylate transport in airway clearance
Authors: Guequen Anita , Tapia-Balladares Bárbara , Villanueva Sandra , Flores Carlos A. 
Published: May 2024

Introduction: Monocarboxylates can be transported by the electrogenic Na+-coupled system (SMCTs/SLC5 family) and the electroneutral H+-coupled system (MCTs/SLC16 family). Previously, MCTs have been described in human bronchial epithelium but there is no evidence of SMCTs activity in airways. We describe here for first time that SMCT1/SCL5A8 is functionally expressed in mouse tracheal epithelium. We hypothesized that monocarboxylate transport activity might downregulate airway clearance in mouse tracheas as increased Na+-absorption reduce airway surface liquid (ASL), and increased H+-secretion acidify ASL. Methods: Short-circuit current ( ISC) recordings were performed in bicarbonate buffer with and without Na+, videomicroscopy of particle track speed (PTS) and mucus transport speed were performed in mouse tracheas. Animals (C57BL6/J) were housed at CECs-Animal facility under controlled temperature, humidity and free access to water and food. All protocols were approved (IACUC, #CECs-2022-04), in accordance with relevant regulations. Results: 10 mM apical L-lactate, D-lactate, pyruvate, propionate or acetate induced a negative current ( ISC~ -35 μA·cm−2; n=4-5 each group) and reduced (p<0.05 rank-sum test) when Na+ was replaced. L-lactate or pyruvate, transported by SMCTs and MCTs increased PTS (2.1±0.1 control vs 3.28±0.4 μm·s−1* for L-lactate and 3.31±0.1 μm·s−1* for pyruvate; n=3 each group; * indicates p<0.05 rank-sum test) and inhibited by 30 μM of the MCT inhibitor AR-C155858 (1.9±0.1 μm·s−1). D-lactate, transported by SMCTs only, did not affected PTS (2.03±0.1 μm·s−1; p>0.05; n=3 each group). We observed a reduction of amiloride-sensitive Na+-absorptive currents in tissues incubated with L-lactate compared to non-incubated ( ISC -17±4 μA·cm−2 vs -5±4 μA·cm−2; p<0.05 rank-sum test; n=4 each group). Finally, analysis of mucus transport determined that L- but not D-lactate increased the speed of mucus, that was prevented when tissues were incubated with AR-C155858 (control 1.06 ± 0.05 μm·s−1 vs L-lactate 1.24 ± 0.08 μm·s−1*, vs L-lactate + AR-C155858 1.02 ± 0.06 μm·s−1; * indicates p<0.05 ANOVA on ranks; n=4 each group). Real time PCR determined that the only SMCT expressed in airway epithelium is SLC5A8. Conclusion: SLC5A8 Na+-dependent D-lactate transport didn't affect mucus clearance. This is explained by the fact that ENaC Na+ absorption competes with SMCTs for basolateral Na+ transport, suggesting that both ENaC and SLC5A8 localize in the same cells. On the other hand, monocarboxylates that increase PTS and mucus speed transport might be explained by MCT-dependent H+ removal (alkalization) from ASL. Since alkalization of the airway surface can restore airway clearance, the use of MCTs transportable substrates might help alleviate mucostasis in muco-obstructive diseases. Funded by FONDECYT 1221257 (C.A.F.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.