Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction

Ueki, Ryusuke; Liu, Li; Kashiwagi, Shizuka; Kaneki, Masao; Khan, Mohammed A S; Hirose, Munetaka; Tompkins, Ronald G.; Martyn, J. A. Jeevendra; Yasuhara, Shingo

doi:10.1097/shk.0000000000000602

Cited by 12 publications

(7 citation statements)

References 43 publications

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“…A recent study from Ueki’s report showed elevated fibrinogen levels in plasma-related muscle wasting in burn mice. They confirmed that fibrinogen increased cytokine TNF and chemokine MCP-1 to further damage mitochondria in myotubes (34). Without mentioning the effect of IL-6, the authors conveyed the complexity of cytokine in triggering mitochondrial disturbances and its effect on muscle homeostasis after burn.…”

Section: Discussionmentioning

confidence: 73%

Burn Serum Stimulates Myoblast Cell Death Associated with IL-6-Induced Mitochondrial Fragmentation

Sehat

Huebinger²,

Carlson

et al. 2017

Shock

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Background: Burn patients suffer muscle mass loss associated with hyperinflammation and hypercatabolism. The mitochondria are affected by this metabolic alteration. Mitochondrial fission activates a caspase cascade that ultimately leads to cell death. We postulate that burn-induced muscle loss is associated with increased mitochondrial fission and subsequent functional impairment. Further, we investigated whether the cytokine IL-6 plays a major role in mitochondrial fission-associated cell death after burn. Methods: Murine myoblast C2C12 cells were treated with 10% serum isolated either from control rats or 40% total body surface area burned rats. Mitochondria were labeled with MitoTracker Green for live cell images. Mitochondrial function was assessed with an Enzo Mito-ID membrane potential cytotoxicity kit. Protein signals were detected by Western blot analysis. Moreover, recombinant IL-6 was applied to stimulate C2C12 to differentiate the role of cytokine IL-6; lastly, we treated burn serum-stimulated cells with IL-6 antibodies. Results: Caspase 3 activity increased in C2C12 cells with burn serum stimulation, suggesting increased cell death in skeletal muscle after burn. Mitochondrial morphology shortened and mitochondrial membrane potential decreased in cells treated with burn serum. Western blot data showed that mitofusion-1 expression significantly decreased in burn serum-treated cells, supporting the morpho-logic observation of mitochondrial fission. Mitochondrial fragmentation increased with IL-6 stimulation, and IL-6 antibody decreased caspase 3 activity and mitochondrial membrane potential improved in burn serum-stimulated cells. Conclusion: Burn serum caused muscle cell death associated with increased mitochondrial fission and functional impairment. This alteration was alleviated with IL-6 antibody treatment, suggesting the cytokine plays a role in mitochondrial changes in muscle after systemic injury.

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Section: Discussionmentioning

confidence: 73%

Burn Serum Stimulates Myoblast Cell Death Associated with IL-6-Induced Mitochondrial Fragmentation

Sehat

Huebinger²,

Carlson

et al. 2017

Shock

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“…Burn injury causes mitochondrial dysfunction 2 – 4 . Next, we studied the effects of FTI on mitochondrial dysfunction in mouse skeletal muscle.…”

Section: Resultsmentioning

confidence: 99%

Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation

Nakazawa

Ikeda

Shinozaki

et al. 2017

Sci Rep

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Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

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“…Fibrinogen, as a pro-inflammatory protein commonly involved in the process of hemostasis, has played an important role in both inflammatory responses and tumor progression and metastasis [ 6 – 8 ]. Numerous studies have reported that fibrinogen level in plasma was upregulated in several types of cancers and related to cancer progression and prognosis [ 9 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

The association of plasma fibrinogen with clinicopathological features and prognosis in esophageal cancer patients

Liu

Gao

et al. 2017

Oncotarget

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BackgroundNumerous studies have shown that plasma fibrinogen was linked to esophageal cancer (EC) risk. However, the clinical significance of plasma fibrinogen in EC patients remain unclear and need to be further clarified.ResultsA total of 2865 patients with EC from 11 published studies were included in this meta-analysis. The prognostic and clinical relevance of plasma fibrinogen were evaluated in EC patients. Statistical significance of the pooled hazard ratio (HR) was found for overall survival (OS), disease free survival (DFS) and recurrence-free survival (RFS) in EC. Subgroup analyses for OS were also performed to confirm the prognostic value of plasma fibrinogen. Additionally, the overall results indicated that elevated plasma fibrinogen was significantly associated with tumor invasion, lymph node metastasis (LNM) and clinical stage.Materials and MethodsA comprehensive literature retrieval was performed in PubMed, Embase, Cochrane database, Web of science and Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases to identify relevant studies published prior to April 15, 2017.ConclusionsElevated plasma fibrinogen could be served as a promising biomarker for predicting a poor prognosis and unfavorable clinicopathologic features for EC.

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Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction

Cited by 12 publications

References 43 publications

Burn Serum Stimulates Myoblast Cell Death Associated with IL-6-Induced Mitochondrial Fragmentation

Burn Serum Stimulates Myoblast Cell Death Associated with IL-6-Induced Mitochondrial Fragmentation

Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation

The association of plasma fibrinogen with clinicopathological features and prognosis in esophageal cancer patients

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