δV1-1 Reduces Pulmonary Ischemia Reperfusion-Induced Lung Injury by Inhibiting Necrosis and Mitochondrial Localization of PKCδ and p53

Kim, H; Zhao, Jinbo; Zhang, Q; Wang, Y; Lee, D; Bai, Xiaohui; Turrell, Lauren; Chen, Mingya; Gao, Wenxi; Keshavjee, Shaf; Liu, Mingyao

doi:10.1111/ajt.13445

Cited by 38 publications

(37 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Their studies show that the inhibition of PKCδ in mice prior to an experimentally induced ischemic event suppresses apoptosis and significantly reduces damage (Bright et al, 2004, 2007; Churchill &Mochly-Rosen, 2007; Churchill et al, 2009). Similar findings have recently been reported for ischemic injury to the lung (Kim et al, 2015, 2016). …”

Section: Biological Functions Of Pkcδsupporting

confidence: 91%

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

View full text Add to dashboard Cite

The serine–threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ−/− mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ−/− mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.

show abstract

Section: Biological Functions Of Pkcδsupporting

confidence: 91%

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

View full text Add to dashboard Cite

show abstract

“…Simulated I/R cell culture model. We simulated pulmonary I/R during lung preservation and transplantation using our cell culture model as previously described (20). To simulate clinical lung preservation, we flushed confluent lung epithelial cells grown in DMEM ϩ 10% FBS at 37°C with ice-cold lung preservation Perfadex solution and incubated them in a 4°C chamber filled with 50% oxygen for 18 h. Cells thereafter were returned to the original cell culture condition (DMEM ϩ 10% FBS at 37°C) for 2 to 4 h to simulate reperfusion.…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial dysfunction assays. Mitochondrial membrane potential was measured using the Tetramethylrhodamine Mitochondrial Membrane Potential Assay Kit (Abcam) (20). Cells were trypsinized and incubated with a working concentration of tetramethylrhodamine ethyl ester for 15 min.…”

Section: Methodsmentioning

confidence: 99%

“…One type of well-described RN is mitochondrial permeability transition pore (MPTP) opening-induced cell death. We recently described that MPTP mediates I/R-induced necrotic cell death, and PKC␦ inhibition reduces necrosis by preventing p53 and PKC␦ translocation to mitochondria (20). Another wellknown RN pathway is necroptosis.…”

Section: Introductionmentioning

confidence: 99%

“…In the present study, we hypothesize that a distinct RN pathway is activated during I/R in LTx settings. Thus, we investigated the pathway using our I/R cell culture model (20) and discovered that prolonged cold ischemic time (CIT) induces caspase-independent cell death associated with mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential loss. These detrimental cellu-lar changes seem to be mediated by RIPK and calpain.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kim

Zamel

Bai

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

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. This calpain-STAT3-RIPK axis induces endoplasmic reticulum stress and mitochondrial calcium dysregulation. LTx patients' samples demonstrate that RIPK1, MLKL, and STAT3 mRNA expression increased from CIT to reperfusion. Moreover, the expressions of the key proteins are higher in PGD samples than in non-PGD samples. Cell death associated with prolonged lung preservation is mediated by the calpain-STAT3-RIPK axis. Inhibition of RIPK and/or calpain pathways could be an effective therapy in LTx.

show abstract

Mechanisms of Cell Death in Ischemia-Reperfusion Injury in Organ Transplantation and Nitric Oxide as a Cytoprotectant

Dugbartey

2024

Gasotransmitters in Organ Transplantation

View full text Add to dashboard Cite

δV1-1 Reduces Pulmonary Ischemia Reperfusion-Induced Lung Injury by Inhibiting Necrosis and Mitochondrial Localization of PKCδ and p53

Cited by 38 publications

References 62 publications

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

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

Mechanisms of Cell Death in Ischemia-Reperfusion Injury in Organ Transplantation and Nitric Oxide as a Cytoprotectant

Contact Info

Product

Resources

About