Organic cation transporters (OCT) 1, 2 and 3 and novel organic cation transporters (OCTN) 1 and 2 of the solute carrier 22 (SLC22) family are involved in the cellular transport of endogenous compounds such as neurotransmitters, l-carnitine and ergothioneine. OCT/Ns have also been implicated in the transport of xenobiotics across various biological barriers, for example biguanides and histamine receptor antagonists. In addition, several drugs used in the treatment of respiratory disorders are cations at physiological pH and potential substrates of OCT/Ns. OCT/Ns may also be associated with the development of chronic lung diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD) and, thus, are possible new drug targets. As part of the Special Issue “Physiology, Biochemistry and Pharmacology of Transporters for Organic Cations”, this review provides an overview of recent findings on the (patho)physiological and pharmacological functions of organic cation transporters in the lung.

The carnitine transporter OCTN2 is associated with asthma and other inflammatory diseases. The aims of this work were (i) to determine carnitine uptake into freshly isolated human alveolar type I (ATI)-like epithelial cells in primary culture, (ii) to compare the kinetics of carnitine uptake between respiratory epithelial in vitro cell models, and (iii) to establish whether any cell line was a suitable model for studies of carnitine transport at the air-blood barrier. Levels of time-dependent [³H]-acetyl-l-carnitine uptake were similar in ATI-like, NCl-H441, and Calu-3 epithelial cells, whereas uptake into A549 cells was ~5 times higher. Uptake inhibition was more pronounced by OCTN2 modulators, such as l-Carnitine and verapamil, in ATI-like primary epithelial cells compared to NCl-H441 and Calu-3 epithelial cells. Our findings suggest that OCTN2 is involved in the cellular uptake of acetyl-l-carnitine at the alveolar epithelium and that none of the tested cell lines are optimal surrogates for primary cells.

SLC26A9 may serve as an alternative epithelial Cl^- channel in cystic fibrosis (CF) to circumvent impaired CFTR-mediated Cl^- secretion. However, the in vivo role of SLC26A9 in lung development remains unclear. Wild-type (WT) and Slc26a9-deficient (Slc26a9^-/-) mice at neonatal age were investigated for oxygen saturation, histology, inflammatory cell count and cytokine levels. Micro-CT imaging and histology was performed to measure airway mucus obstruction. Transepithelial potential differences (PD) of cultured murine tracheal explants were assessed. The mortality of Slc26a9^-/- mice was significantly increased to 52% compared to WT mice (p<0.05). The oxygen saturation was strongly diminished in Slc26a9^-/- vs. WT mice (p< 0.01). Histological analyses demonstrated an increased mucus volume in the trachea, proximal and distal airways of Slc26a9^-/- mice (p< 0.01). Micro-CT imaging confirmed severe airway mucus obstruction. Functionally, basal PD was decreased in Slc26a9^-/- vs. WT mice (p< 0.05). Levels of IL-1α and IL-1β were significantly augmented (p< 0.01). The inflammatory phenotype was further specified by elevated numbers of neutrophils (p< 0.05) and significantly increased levels of MIP-2 and KC in Slc26a9^-/- mice vs. WT mice (p<0.01). Taken together, Slc26a9^-/- neonates show an early onset of airway mucus obstruction and increased mortality accompanied with neutrophilic inflammation. Our data support that SLC26A9-mediated Cl^- secretion is critical for airway mucus clearance in the neonatal lung and may be a target to modulate the pathogenesis of muco-obstructive lung diseases.