title: Sirtuin 1 Agonist Minimizes Injury and Improves the Immune Response Following Traumatic Shock.
abstract: Survival from traumatic injury requires a coordinated and controlled inflammatory and immune response. Mitochondrial and metabolic responses to stress have been shown to play a role in these inflammatory and immune responses. We hypothesized that increases in mitochondrial biogenesis via a sirtuin 1 agonist would decrease tissue injury and partially ameliorate the immunosuppression seen following trauma. C57Bl/6 mice were subjected to a multiple trauma model. Mice were pretreated with either 100 mg/kg per day of the sirtuin 1 agonist, Srt1720, via oral gavage for 2 days prior to trauma and extended until the day the animals were killed, or they were pretreated with peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) siRNA via hydrodynamic tail vein injection 48 h prior to trauma. Markers for mitochondrial function and biogenesis were measured in addition to splenocyte proliferative capacity and bacterial clearance. Srt1720 was noted to improve mitochondrial biogenesis, mitochondrial function, and complex IV activity following traumatic injury (P < 0.05), whereas knockdown of PGC1α resulted in exacerbation of mitochondrial dysfunction (P < 0.05). These changes in mitochondrial function were associated with altered severity of hepatic injury with significant reductions in serum alanine aminotransferase levels seen in mice treated with srt1720. Splenocyte proliferative capacity and intraperitoneal bacterial clearance were evaluated as markers for overall immune function following trauma-hemorrhage. Treatment with Srt1720 minimized the trauma-induced decreases in splenocyte proliferation (P < 0.05), whereas treatment with PGC1α siRNA led to diminished bacterial clearance. The PGC1α signaling pathway is an important regulator of mitochondrial function and biogenesis, which can potentially be harnessed to protect against hepatic injury and minimize the immunosuppression that is seen following trauma-hemorrhage.
authors.affiliation: *Department of Surgery, University of Pittsburgh; †VA Pittsburgh Healthcare System; Departments of ‡Critical Care Medicine and §Pharmacology & Chemical Biology, ∥Vascular Medicine Institute, and ¶The Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Luciano
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kautza
authors.forename: Sophie
authors.initials: S
authors.lastname: Darwiche
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinez
authors.forename: Sladjana
authors.initials: S
authors.lastname: Stratimirovic
authors.forename: Paul
authors.initials: P
authors.lastname: Waltz
authors.forename: Jason
authors.initials: J
authors.lastname: Sperry
authors.forename: Matthew
authors.initials: M
authors.lastname: Rosengart
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D004926:Escherichia coli; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D057446:Hydrodynamics; D007107:Immune System; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism; D010537:Peritoneum / Q000382:microbiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering / Q000378:metabolism; D012774:Shock, Traumatic / Q000276:immunology* / Q000628:therapy*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000737:chemistry*; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000737:chemistry
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; C525422:SRT1720; D014157:Transcription Factors; D000410:Alanine Transaminase; D056564:Sirtuin 1