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Everolimus-induced hyperpermeability of endothelial cells causes lung injury.
Chen, Xiaolin; Chen, Jianhui; Liu, Shuihong; Li, Xianfan.
Afiliação
  • Chen X; Department of Clinical Laboratory, Pingxiang People's Hospital, Pingxiang 337000, China.
  • Chen J; Department of Clinical Laboratory, The Sixth Clinical College of Gannan Medical University, Pingxiang 337000, China.
  • Liu S; Department of Clinical Laboratory, Pingxiang People's Hospital, Pingxiang 337000, China.
  • Li X; Department of Clinical Laboratory, Pingxiang People's Hospital, Pingxiang 337000, China.
Exp Biol Med (Maywood) ; 248(23): 2440-2448, 2023 Dec.
Article em En | MEDLINE | ID: mdl-38158699
ABSTRACT
The mammalian target of rapamycin (mTOR) inhibitors, everolimus (but not dactolisib), is frequently associated with lung injury in clinical therapies. However, the underlying mechanisms remain unclear. Endothelial cell barrier dysfunction plays a major role in the pathogenesis of the lung injury. This study hypothesizes that everolimus increases pulmonary endothelial permeability, which leads to lung injury. We tested the effects of everolimus on human pulmonary microvascular endothelial cell (HPMEC) permeability and a mouse model of intraperitoneal injection of everolimus was established to investigate the effect of everolimus on pulmonary vascular permeability. Our data showed that everolimus increased human pulmonary microvascular endothelial cell (HPMEC) permeability which was associated with MLC phosphorylation and F-actin stress fiber formation. Furthermore, everolimus induced an increasing concentration of intracellular calcium Ca2+ leakage in HPMECs and this was normalized with ryanodine pretreatment. In addition, ryanodine decreased everolimus-induced phosphorylation of PKCα and MLC, and barrier disruption in HPMECs. Consistent with in vitro data, everolimus treatment caused a visible lung-vascular barrier dysfunction, including an increase in protein in BALF and lung capillary-endothelial permeability, which was significantly attenuated by pretreatment with an inhibitor of PKCα, MLCK, and ryanodine. This study shows that everolimus induced pulmonary endothelial hyper-permeability, at least partly, in an MLC phosphorylation-mediated EC contraction which is influenced in a Ca2+-dependent manner and can lead to lung injury through mTOR-independent mechanisms.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Endoteliais / Lesão Pulmonar Limite: Animals / Humans Idioma: En Revista: Exp Biol Med (Maywood) Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Endoteliais / Lesão Pulmonar Limite: Animals / Humans Idioma: En Revista: Exp Biol Med (Maywood) Ano de publicação: 2023 Tipo de documento: Article