title: Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice.
abstract: OBJECTIVE
  Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis.
  
  
  METHODS
  Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a "second-hit" (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis.
  
  
  RESULTS
  We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65.
  
  
  CONCLUSIONS
  SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis.
authors: Departments of Anesthesiology Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
authors: Xianfeng
authors: X
authors: Wang
authors: Departments of Anesthesiology Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
authors: Nancy L
authors: NL
authors: Buechler
authors: Department of Medicine Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
authors: Ayana
authors: A
authors: Martin
authors: Department of Surgery Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
authors: Jonathan
authors: J
authors: Wells
authors: Department of Medicine Wake Forest School of Medicine, Winston-Salem, NC, United States of America.|Department of Surgery Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
authors: Barbara
authors: B
authors: Yoza
authors: Department of Medicine Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
authors: Charles E
authors: CE
authors: McCall
authors: Departments of Anesthesiology Wake Forest School of Medicine, Winston-Salem, NC, United States of America.|Department of Medicine Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
authors: Vidula
authors: V
authors: Vachharajani
mesh_terms: D000818:Animals; D002460:Cell Line; D004731:Endotoxins / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D055806:Microvessels / Q000378:metabolism / Q000503:physiopathology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D018805:Sepsis / Q000209:etiology* / Q000276:immunology / Q000401:mortality; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D004731:Endotoxins; D051996:Transcription Factor RelA; C470545:Sirt1 protein, mouse; C418743:Sirt2 protein, mouse; D056564:Sirtuin 1; D056565:Sirtuin 2