Pharmacological Sirt1 Activation Improves Mortality and Markedly Alters Transcriptional Profiles That Accompany Experimental Sepsis

Abstract

The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025's effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection.

SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model

“…Recently, a study showed that SIRT1 knockdown mice exhibited aggravated inflammatory signaling such as NF-kappa B in lung tissue of CLP mice [10]. Furthermore, pharmacological SIRT1 activation decreased mortality in experimental sepsis [24]. Importantly, RSV was found to effectively inhibit inflammatory responses by acting as a SIRT1 activator [25].…”

“…Through deacetylation of histone and nonhistone substrate, SIRT1 is involved in various metabolic and inflammatory diseases [8, 9]. Interestingly, SIRT1 activity is decreased in the liver, spleen, small bowel, and lung tissue in experimental sepsis models, and SIRT1 activation could improve the outcome of sepsis and ameliorate the associated inflammatory response [10, 11]. Besides SIRT1, another sirtuin, SIRT3, has also received considerable attention [12, 13].…”

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

“…have demonstrated that oral administration of SRT3025, another STAC, significantly improves a 7-day survival of septic mice induced by CLP. 19 Although in their study SRT3025 is given starting 48 h before CLP, we administered SRT1720 at 5 h after CLP. Resveratrol, a less specific Sirt1 activator, reduces AST, ALT, and histologic liver damage in septic rats induced by CLP 31 , and it decreases pulmonary edema and lung pathological alterations in the mouse model of sepsis induced by lipopolysaccharide (LPS).…”

“…31,32 Moreover, stimulation of Sirt1 by SRT3025 reduces the levels of proinflammatory cytokines in the lungs of animals challenged with S. pneumoniae . 19 Macrophages are the major source of proinflammatory cytokines after activation. An in vitro study demonstrated that enhancing the Sirt1 expression inhibits the secretion of IL-6 and TNF-α in murine macrophages stimulated with LPS.…”

“…18 STAC treatment before and through sepsis induction has shown beneficial effects 19 . However, the effect of STAC treatment after sepsis induction, which more closely resembles clinical therapy, has not been evaluated.…”