title: Treatment with gelsolin reduces brain inflammation and apoptotic signaling in mice following thermal injury.
abstract: BACKGROUND
  Burn survivors develop long-term cognitive impairment with increased inflammation and apoptosis in the brain. Gelsolin, an actin-binding protein with capping and severing activities, plays a crucial role in the septic response. We investigated if gelsolin infusion could attenuate neural damage in burned mice.
  
  
  METHODS
  Mice with 15% total body surface area burns were injected intravenously with bovine serum albumin as placebo (2 mg/kg), or with low (2 mg/kg) or high doses (20 mg/kg) of gelsolin. Samples were harvested at 8, 24, 48 and 72 hours postburn. The immune function of splenic T cells was analyzed. Cerebral pathology was examined by hematoxylin/eosin staining, while activated glial cells and infiltrating leukocytes were detected by immunohistochemistry. Cerebral cytokine mRNAs were further assessed by quantitative real-time PCR, while apoptosis was evaluated by caspase-3. Neural damage was determined using enzyme-linked immunosorbent assay of neuron-specific enolase (NSE) and soluble protein-100 (S-100). Finally, cerebral phospho-ERK expression was measured by western blot.
  
  
  RESULTS
  Gelsolin significantly improved the outcomes of mice following major burns in a dose-dependent manner. The survival rate was improved by high dose gelsolin treatment compared with the placebo group (56.67% vs. 30%). Although there was no significant improvement in outcome in mice receiving low dose gelsolin (30%), survival time was prolonged against the placebo control (43.1 ± 4.5 h vs. 35.5 ± 5.0 h; P < 0.05). Burn-induced T cell suppression was greatly alleviated by high dose gelsolin treatment. Concurrently, cerebral abnormalities were greatly ameliorated as shown by reduced NSE and S-100 content of brain, decreased cytokine mRNA expressions, suppressed microglial activation, and enhanced infiltration of CD11b+ and CD45+ cells into the brain. Furthermore, the elevated caspase-3 activity seen following burn injury was remarkably reduced by high dose gelsolin treatment along with down-regulation of phospho-ERK expression.
  
  
  CONCLUSIONS
  Exogenous gelsolin infusion improves survival of mice following major burn injury by partially attenuating inflammation and apoptosis in brain, and by enhancing peripheral T lymphocyte function as well. These data suggest a novel and effective strategy to combat excessive neuroinflammation and to preserve cognition in the setting of major burns.
authors.affiliation: Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, PR China.
authors.forename: Qing-Hong
authors.initials: QH
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Jia-Rui
authors.initials: JR
authors.lastname: Kang
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Dong
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Zhu
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Sheng
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Yao
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D002056:Burns / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002417:Cattle; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018260:Gelsolin / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000166:cytology / Q000276:immunology; D011897:Random Allocation; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D015703:Antigens, CD; D061945:Caspase Inhibitors; D016207:Cytokines; D018260:Gelsolin; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3