SRT1720, a sirtuin 1 activator, attenuates organ injury and inflammation in sepsis

Adam Khader, Weng Lang Yang, Laura W. Hansen, Salil R. Rajayer, Jose M. Prince, Jeffrey M. Nicastro, Gene F. Coppa, Ping Wang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background Sepsis affects 800,000 patients in the United States annually with a mortality rate of up to 30%. Recent studies suggest that sepsis-associated metabolic derangements due to hypoxic tissue injury, impaired oxygen utilization, and mitochondrial dysfunction contribute to mortality. Sirtuin 1 (Sirt1) is a crucial modulator of energy metabolism during starvation states and has anti-inflammatory effects. Here, we hypothesized that SRT1720, a Sirt1 activator, could attenuate the severity of sepsis. Materials and methods Male C57BL/6 mice (20-25 g) were subjected to cecal ligation and puncture (CLP) to induce sepsis. SRT1720 (5 or 20 mg/kg BW) or 10% dimethyl sulfoxide (vehicle) in 0.2-mL saline was injected intravenously at 5 h after CLP. Control animals were not subjected to any surgery. Blood and liver samples were harvested at 20 h after CLP for analysis. Results Administration of SRT1720 markedly reduced the serum levels of tissue injury markers (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) and renal injury markers (blood urea nitrogen and creatinine) in a dose-dependent manner after CLP. Furthermore, the levels of proinflammatory cytokines interleukin (IL)-1β and IL-6 in the serum and liver were significantly inhibited by SRT1720 treatment after CLP. SRT1720 treatment resulted in a significantly decreased mRNA expression of inflammasome components (nucleotide oligomerization domain–like receptor protein 3, adapter apoptosis-associated speck-like protein containing caspase-recruitment domain, IL-1β, and IL-18) in the liver, compared with the vehicle group. Conclusions SRT1720 treatment attenuates multiorgan injury in septic mice. SRT1720 treatment also decreases the production of proinflammatory cytokines and reduces inflammasome activation. Thus, pharmacologic stimulation of Sirt1 may present a promising therapeutic strategy for sepsis.

Original languageEnglish (US)
Pages (from-to)288-295
Number of pages8
JournalJournal of Surgical Research
Volume219
DOIs
StatePublished - Nov 2017
Externally publishedYes

Keywords

  • Inflammasome
  • Inflammation
  • Organ injury
  • Sepsis
  • Sirtuin 1
  • SRT1720

ASJC Scopus subject areas

  • Surgery

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