Abstract
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.
Highlights
Organic cation transporters (i.e., OCT1, OCT2, and OCT3, encoded by SLC22A1–3) and novel organic cation transporters (i.e., OCTN1 and OCTN2, encoded by SLC22A4–5) play important roles in thephysiological membrane transport of endogenous and exogenous substrates, including drugs [1,2]
Genetic studies revealed that variants of OCTN2 are associated with asthma [7,8]; expression of OCTN1 and OCNT2 was not altered in lung tissues from patients with chronic obstructive pulmonary disease (COPD) [9]
In search for a suitable in vitro model for studying OCTN2 at the human alveolar epithelial barrier, we further investigated similarities and differences in OCTN2 activity between alveolar type I (ATI)-like primary cells and respiratory epithelial cell lines (i.e., A549, NCl-H441, and Calu-3)
Summary
Organic cation transporters (i.e., OCT1, OCT2, and OCT3, encoded by SLC22A1–3) and novel organic cation transporters (i.e., OCTN1 and OCTN2, encoded by SLC22A4–5) play important roles in the (patho-)physiological membrane transport of endogenous and exogenous substrates, including drugs [1,2]. In vivo data showed that tracheal accumulation of the anticholinergic bronchodilator ipratropium was inhibited by both carnitine and 1-methyl-4-phenylpyridinium (MPP+), OCTN2 (and probably OCT2) involvement in the process was suggested [6]. Challenge with lipopolysaccharide (LPS) and house dust mites significantly upregulated OCTN2 expression in Calu-3 cells in vitro, suggesting that allergic airway inflammation impacts the inhaled drug disposition via OCTN2 [22]. Al-Jayyoussi et al showed that OCT/Ns were involved in the cellular accumulation of the substrate ipratropium and l-carnitine in human respiratory epithelial cell models; no carnitine-sensitive pulmonary absorption was observed using an intact, isolated, perfused rat-lung model [23]
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