title: 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.
authors.affiliation: *Infectious Disease Division, Memorial Hospital of RI, Pawtucket †The Alpert Medical School of Brown University, Providence, Rhode Island ‡Sirtris, A GSK company, Cambridge, Massachusetts §GlaxoSmithKline, Collegeville, Pennsylvania ||GlaxoSmithKline, Research Triangle Park, North Carolina ¶Pathology Department, Memorial Hospital of RI, Pawtucket, Rhode Island.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
authors.forename: James L
authors.initials: JL
authors.lastname: Ellis
authors.forename: Vipin
authors.initials: V
authors.lastname: Suri
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Freudenberg
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Abdullah B
authors.initials: AB
authors.lastname: Chahin
authors.forename: John E
authors.initials: JE
authors.lastname: Palardy
authors.forename: Nicholas
authors.initials: N
authors.lastname: Parejo
authors.forename: Michelle
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Chahin
authors.forename: Noubar
authors.initials: N
authors.lastname: Kessimian
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D051379:Mice; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D056564:Sirtuin 1 / Q000276:immunology*; D013290:Streptococcal Infections / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013296:Streptococcus pneumoniae; D013844:Thiazoles / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
chemical_list: D000813:Anilides; C000601293:SRT3025; D013844:Thiazoles; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1