Hydroxypropyl Cyclodextrin Improves Amiodarone-induced Aberrant Lipid Homeostasis of Alveolar Cells

Abstract

Alveolar epithelial type II (AT2) cells secrete pulmonary surfactant via lamellar bodies (LBs).Abnormalities in LBs are associated with pulmonary disorders, including fibrosis. However, high-content screening (HCS) for LB abnormalities is limited by the lack of understanding of AT2 cell functions. In the present study, we have developed LB cells harboring LB-like organelles that secrete surfactant proteins. These cells were more similar to AT2 cells than to parental A549 cells. LB cells recapitulated amiodarone (AMD)-induced LB enlargement, similar to AT2 cells of patients exposed to AMD. To reverse AMD-induced LB abnormalities, we performed HCS of approved drugs and identified 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cyclic oligosaccharide, as a potential therapeutic agent. A transcriptome analysis revealed that HPβCD modulates lipid homeostasis. In addition, HPβCD inhibited AMD-induced LB abnormalities in human induced pluripotent stem cell-derived AT2 cells. Our results demonstrate that LB cells are useful for HCS, and suggest that HPβCD is a candidate therapeutic agent for AMD-induced interstitial pneumonia.

Repurposing A549 Adenocarcinoma Cells: New Options for Drug Discovery

“…The authors developed a high-content screening (HCS) assay for lamellar bodies using LB cells, and used it to screen several compounds from the Kyoto University Chemistry library. This led to the identification of HPβCD as a candidate therapeutic agent for AMD-induced interstitial pneumonia, validating their results using iPSC-derived alveolar organoids (18).…”

“…specific to AT2, was lower in LB cells. However, the expression patterns in LB cells were more similar to those in primary AT2 cells than in "wild type" A549 cells (18). Next, they treated the LB cells with amiodarone (AMD).…”

Disease modeling of pulmonary fibrosis using human pluripotent stem cell-derived alveolar organoids

“…These organoids could be expanded in the long term, and consisted of multi-lineage epithelial cells derived from hPSCs and fibroblasts. Our previous reports on AT2 cell dysfunction associated with amiodarone (AMD)-induced and Hermansky-Pudlak syndrome type 2-related pulmonary fibrosis lacked a demonstration of the phenotypes of pulmonary fibrosis or activated fibroblasts associated with epithelial cell injury (Kanagaki et al, 2021b;Korogi et al, 2019). Here, we developed a novel pulmonary fibrosis model in vitro using surfactant protein C-positive (SPC + ) cellderived FD-AOs upon bleomycin (BLM) treatment.…”

Perspectives of future lung toxicology studies using human pluripotent stem cells

“…Kanagaki et al reconstructed lamellar body (LB)-like organelles in A549 cells exogenously expressing surfactant protein genes. Those “LB cells” were able to simulate the secretion of surfactant proteins (Kanagaki et al 2021b ), and were useful in evaluating the abnormalities of lamellar bodies and identifying a potential therapeutic agent. Microfluidic technology has contributed to recapitulating the pulmonary vascular barrier in the co-culture of endothelial cells and A549 cells on a chip (Huh et al 2010 ).…”