In Vivo Evidence of Organic Cation Transporter-Mediated Tracheal Accumulation of the Anticholinergic Agent Ipratropium in Mice

Nakanishi, Takeo; Hasegawa, Yoshitaka; Haruta, Tsunemitsu; Wakayama, Tomohiko; Tamai, Ikumi

doi:10.1002/jps.23603

Cited by 18 publications

(17 citation statements)

References 29 publications

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“…As far as human lung is concerned, OCTN2 expression has been detected in several respiratory epithelial models, such as A549, 16HBE14o -, BEAS-2B, NCI-H292, NCI-H441, as well as Calu-3 cells [11,12,13,14,15]. Recently, OCTN2 has been included in the catalog of transporters responsible for the interaction with drugs by the International Transporter Consortium (ITC) [16]; its involvement in the transport of bronchodilators has been also suggested [17,18].…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of OCTN2 and ATB0,+ in normal human airway epithelial cells

et al. 2020

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In human, OCTN2 (SLC22A5) and ATB 0,+ (SLC6A14) transporters mediate the uptake of Lcarnitine, essential for the transport of fatty acids into mitochondria and the subsequent degradation by β-oxidation. Aim of the present study was to characterize L-carnitine transport in EpiAirway™, a 3D organotypic in vitro model of primary human tracheal-bronchial epithelial cells that form a fully differentiated, pseudostratified columnar epithelium at air-liquid interface (ALI) condition. In parallel, Calu-3 monolayers grown at ALI for different times (8d or 21d of culture) were used as comparison. OCTN2 transporter was equally expressed in both models and functional at the basolateral side. ATB 0,+ was, instead, highly expressed and active on the apical membrane of EpiAirway™ and only in early-cultures of Calu-3 (8d but not 21d ALI). In both cell models, L-carnitine uptake on the apical side was significantly inhibited by the bronchodilators glycopyrrolate and tiotropium, that hence can be considered substrates of ATB 0,+ ; ipratropium was instead effective on the basolateral side, indicating its interaction with OCTN2. Inflammatory stimuli, such as LPS or TNFα, caused an induction of SLC6A14/ATB 0,+ expression in Calu-3 cells, along with a 2-fold increase of L-carnitine uptake only at the apical side; on the contrary SLC22A5/OCTN2 was not affected. As both OCTN2 and ATB 0,+ , beyond transporting L-carnitine, have a significant potential as delivery systems for drugs, the identification of these transporters in EpiAirway™ can open new fields of investigation in the study of drug inhalation and pulmonary delivery. M, et al. (2020) Functional analysis of OCTN2 and ATB 0,+ in normal human airway epithelial cells. PLoS ONE 15(2): e0228568.

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Section: Introductionmentioning

confidence: 99%

Functional analysis of OCTN2 and ATB0,+ in normal human airway epithelial cells

et al. 2020

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“…Immunohistochemical examination was basically carried out as described previously [ 31 ]. After acclimation, WT (C57BL/6) mice (23.4 ± 0.65 g, at age of 7 to 9 weeks) were anesthetized with an intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis

Nakanishi

Hasegawa

et al. 2015

PLoS ONE

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Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1 -/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1 -/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1 -/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1 -/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1 -/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1 -/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1 -/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

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“…OCT physiology in tissues such as the liver, gut and kidneys has by and large been well characterised (Nies et al, 2011), nonetheless, the lungs remain somewhat understudied in this regard. Moreover, OCT expression data concerning the respiratory epithelium is often limited to gene or PCR-based in vitro studies (Bleasby et al, 2006;Courcot et al, 2012;Endter et al, 2009;Mukherjee et al, 2012) and only a small number of reports show OCT immunocytochemistry or indeed transporter function (Lips et al 2005;Macdonald et al, 2013;Nakanishi et al, 2013). Very recently, it has been shown by our group that β 2 agonists interact with OCT at the lung epithelium (Salomon et al, 2015), however, the clinical relevance of these findings are not fully understood to date.…”

Section: Introductionmentioning

confidence: 96%