title: Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction: Protective Effects of Glycyrrhizin.
abstract: Skeletal muscle wasting and weakness with mitochondrial dysfunction (MD) are major pathological problems in burn injury (BI) patients. Fibrinogen levels elevated in plasma is an accepted risk factor for poor prognosis in many human diseases, and is also designated one of damage-associated molecular pattern (DAMPs) proteins. The roles of upregulated fibrinogen on muscle changes of critical illness including BI are unknown. The hypothesis tested was that BI-upregulated fibrinogen plays a pivotal role in the inflammatory responses and MD in muscles, and that DAMPs inhibitor, glycyrrhizin mitigates the muscle changes.
  
  
  
  After third degree BI to mice, fibrinogen levels in the plasma and at skeletal muscles were compared between BI and sham-burn (SB) mice. Fibrinogen effects on inflammatory responses and mitochondrial membrane potential (MMP) loss were analyzed in C2C12 myotubes. In addition to survival, the anti-inflammatory and mitochondrial protective effects of glycyrrhizin were tested using in vivo microscopy of skeletal muscles of BI and SB mice.
  
  
  
  Fibrinogen in plasma and its extravasation to muscles significantly increased in BI versus SB mice. Fibrinogen applied to myotubes evoked inflammatory responses (increased MCP-1 and TNF-α; 32.6 and 3.9-fold, respectively) and reduced MMP; these changes were ameliorated by glycyrrhizin treatment. In vivo MMP loss and superoxide production in skeletal muscles of BI mice were significantly attenuated by glycyrrhizin treatment, together with improvement of BI survival rate.
  
  
  
  Inflammatory responses and MMP loss in myotubes induced by fibrinogen were reversed by glycyrrhizin. Anti-inflammatory and mitochondrial protective effect of glycyrrhizin in vivo leads to amelioration of muscle MD and improvement of BI survival rate.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; Shriners Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Department of Anesthesiology and Pain Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Ueki
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Shizuka
authors.initials: S
authors.lastname: Kashiwagi
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
authors.forename: Mohammed A S
authors.initials: MA
authors.lastname: Khan
authors.forename: Munetaka
authors.initials: M
authors.lastname: Hirose
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.forename: Jeevendra A J
authors.initials: JA
authors.lastname: Martyn
authors.forename: Shingo
authors.initials: S
authors.lastname: Yasuhara
mesh_terms: D000818:Animals; D002056:Burns / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005340:Fibrinogen / Q000378:metabolism* / Q000494:pharmacology; D019695:Glycyrrhizic Acid / Q000627:therapeutic use*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D019695:Glycyrrhizic Acid; D005340:Fibrinogen