Specific p38 inhibition in stimulated endothelial cells: A possible new anti-inflammatory strategy after hypothermia and rewarming

Diestel, Antje; Roessler, Joerg; Pohl-Schickinger, A.; Koster, Andreas; Drescher, Cornelia; Berger, Felix; Schmitt, Katharina

doi:10.1016/j.vph.2009.06.006

Cited by 16 publications

(8 citation statements)

References 36 publications

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“…This inhibition of the phosphorylated p38 protein occurred despite the significant upregulation at the mRNA level of known p38 activators such as MAPK3K4 (Takekawa et al, 1997 ), MAP2K3 (Raingeaud et al, 1996 ), and MAPKAPK2 (Rousseau et al, 2002 ; Tollenaere et al, 2015 ). Hypothermia mediated suppression of p38 activation suggests that hypothermia could mediate part of its neuroprotective effect via inhibiting inflammation (Diestel et al, 2009 ), cellular death and apoptosis (Yang et al, 2010 ). Thus, there is some indication that p38 inhibition could be a promising therapeutic target for hypothermia-mediated anti-inflammatory effects and for reducing brain injury and neurological pathology during the acute phase of cytotoxic edema (Barone et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Gene Expression Provides New Insights into the Effect of Mild Therapeutic Hypothermia on Primary Human Cortical Astrocytes Cultured under Hypoxia

Salman

Kitchen

Woodroofe

et al. 2017

Front. Cell. Neurosci.

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Hypothermia is increasingly used as a therapeutic measure to treat brain injury. However, the cellular mechanisms underpinning its actions are complex and are not yet fully elucidated. Astrocytes are the most abundant cell type in the brain and are likely to play a critical role. In this study, transcriptional changes and the protein expression profile of human primary cortical astrocytes cultured under hypoxic conditions for 6 h were investigated. Cells were treated either with or without a mild hypothermic intervention 2 h post-insult to mimic the treatment of patients following traumatic brain injury (TBI) and/or stroke. Using human gene expression microarrays, 411 differentially expressed genes were identified following hypothermic treatment of astrocytes following a 2 h hypoxic insult. KEGG pathway analysis indicated that these genes were mainly enriched in the Wnt and p53 signaling pathways, which were inhibited following hypothermic intervention. The expression levels of 168 genes involved in Wnt signaling were validated by quantitative real-time-PCR (qPCR). Among these genes, 10 were up-regulated and 32 were down-regulated with the remainder unchanged. Two of the differentially expressed genes (DEGs), p38 and JNK, were selected for validation at the protein level using cell based ELISA. Hypothermic intervention significantly down-regulated total protein levels for the gene products of p38 and JNK. Moreover, hypothermia significantly up-regulated the phosphorylated (activated) forms of JNK protein, while downregulating phosphorylation of p38 protein. Within the p53 signaling pathway, 35 human apoptosis-related proteins closely associated with Wnt signaling were investigated using a Proteome Profiling Array. Hypothermic intervention significantly down-regulated 18 proteins, while upregulating one protein, survivin. Hypothermia is a complex intervention; this study provides the first detailed longitudinal investigation at the transcript and protein expression levels of the molecular effects of therapeutic hypothermic intervention on hypoxic human primary cortical astrocytes. The identified genes and proteins are targets for detailed functional studies, which may help to develop new treatments for brain injury based on an in-depth mechanistic understanding of the astrocytic response to hypoxia and/or hypothermia.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Gene Expression Provides New Insights into the Effect of Mild Therapeutic Hypothermia on Primary Human Cortical Astrocytes Cultured under Hypoxia

Salman

Kitchen

Woodroofe

et al. 2017

Front. Cell. Neurosci.

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“…Addition of a p38 MAPK inhibitor to the Celsior solution enhanced the viability of cardiac grafts from non-heart-beating donors in a canine model of heart transplantation [225]. Moreover, p38 MAPK blockade attenuated the release of proinflammatory IL-6 by human endothelial cells in vitro after cooling and rewarming [226]. p38 MAPK inhibition similarly prevented endothelial adhesion molecule expression and polymorphonuclear accumulation after myocardial IR injury in rats [74].…”

Section: Mapk Inhibition In Experimental Heart Transplantationmentioning

confidence: 99%

Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation

Vassalli

Milano

Moccetti

2012

Journal of Transplantation

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In solid organ transplantation, ischemia/reperfusion (IR) injury during organ procurement, storage and reperfusion is an unavoidable detrimental event for the graft, as it amplifies graft inflammation and rejection. Intracellular mitogen-activated protein kinase (MAPK) signaling pathways regulate inflammation and cell survival during IR injury. The four best-characterized MAPK subfamilies are the c-Jun NH2-terminal kinase (JNK), extracellular signal- regulated kinase-1/2 (ERK1/2), p38 MAPK, and big MAPK-1 (BMK1/ERK5). Here, we review the role of MAPK activation during myocardial IR injury as it occurs during heart transplantation. Most of our current knowledge regarding MAPK activation and cardioprotection comes from studies of preconditioning and postconditioning in nontransplanted hearts. JNK and p38 MAPK activation contributes to myocardial IR injury after prolonged hypothermic storage. p38 MAPK inhibition improves cardiac function after cold storage, rewarming and reperfusion. Small-molecule p38 MAPK inhibitors have been tested clinically in patients with chronic inflammatory diseases, but not in transplanted patients, so far. Organ transplantation offers the opportunity of starting a preconditioning treatment before organ procurement or during cold storage, thus modulating early events in IR injury. Future studies will need to evaluate combined strategies including p38 MAPK and/or JNK inhibition, ERK1/2 activation, pre- or postconditioning protocols, new storage solutions, and gentle reperfusion.

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“…Data from Schmitt and colleagues suggest that pretreatment with methylprednisolone increases cerebral cell survival after deep hypothermia [50], but also suppresses important neuroprotective and regenerative processes induced by the proinflammatory cytokine IL-6. Diestel and colleagues focused on endothelial cells [56], which maintain systemic inflammation via cytokine production. Only combined pretreatment with methylprednisolone and tacrolimus inhibited IL-6 secretion.…”

Section: Systemic Inflammationmentioning

confidence: 99%

Rewarming: facts and myths from the systemic perspective

2012

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Specific p38 inhibition in stimulated endothelial cells: A possible new anti-inflammatory strategy after hypothermia and rewarming

Cited by 16 publications

References 36 publications

Transcriptome Analysis of Gene Expression Provides New Insights into the Effect of Mild Therapeutic Hypothermia on Primary Human Cortical Astrocytes Cultured under Hypoxia

Transcriptome Analysis of Gene Expression Provides New Insights into the Effect of Mild Therapeutic Hypothermia on Primary Human Cortical Astrocytes Cultured under Hypoxia

Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation

Rewarming: facts and myths from the systemic perspective

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