Ischemia-reperfusion induces death receptor-independent necroptosis via calpain-STAT3 activation in a lung transplant setting

American Journal of Physiology. Lung Cellular and Molecular Physiology
Hyunhee KimMingyao Liu

Abstract

Ischemia-reperfusion (I/R)-induced lung injury undermines lung transplantation (LTx) outcomes by predisposing lung grafts to primary graft dysfunction (PGD). Necrosis is a feature of I/R lung injury. However, regulated necrosis (RN) with specific signaling pathways has not been explored in an LTx setting. In this study, we investigated the role of RN in I/R-induced lung injury. To study I/R-induced cell death, we simulated an LTx procedure using our cell culture model with human lung epithelial (BEAS-2B) cells. After 18 h of cold ischemic time (CIT) followed by reperfusion, caspase-independent cell death, mitochondrial reactive oxygen species production, and mitochondrial membrane permeability were significantly increased. N-acetyl-Leu-Leu-norleucinal (ALLN) (calpain inhibitor) or necrostatin-1 (Nec-1) [receptor interacting serine/threonine kinase 1 (RIPK1) inhibitor] reduced these changes. ALLN altered RIPK1/RIPK3 expression and mixed lineage kinase domain-like (MLKL) phosphorylation, whereas Nec-1 did not change calpain/calpastatin expression. Furthermore, signal transducer and activator of transcription 3 (STAT3) was demonstrated to be downstream of calpain and regulate RIPK3 expression and MLKL phosphorylation during I/R. T...Continue Reading

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Citations

Mar 26, 2019·American Journal of Respiratory Cell and Molecular Biology·Natalia F Smirnova, Oliver Eickelberg
Aug 17, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Paras K MishraTakashi Matsui
Jun 6, 2019·Journal of Neurochemistry·Enrique Font-BelmonteArsenio Fernández-López
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Mar 20, 2021·Photodermatology, Photoimmunology & Photomedicine·Ziting TangShengbo Yang
Mar 3, 2021·American Journal of Respiratory Cell and Molecular Biology·Sagar Paudel, Samithamby Jeyaseelan
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Mar 11, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Lei JingMingyao Liu
May 23, 2021·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·Hailey M ShepherdDaniel Kreisel
Nov 10, 2020·Acta Pharmaceutica Sinica. B·Aqu AluXiawei Wei

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Methods Mentioned

BETA
flow cytometry
Assay
transfection
coimmunoprecipitation
biopsy
biopsies
Chip
pulled down
ubiquitination

Software Mentioned

R : A Language and Environment for Statistical Computing
R
R Core Team
GraphPad Prism
FlowJo
STATTIC
Brainarray
R Foundation for Statistical Computing
affy package

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