PMID- 38015645
OWN - NLM
STAT- MEDLINE
DCOM- 20231130
LR  - 20231201
IS  - 1557-8674 (Electronic)
IS  - 1096-2964 (Print)
IS  - 1096-2964 (Linking)
VI  - 24
IP  - 9
DP  - 2023 Nov
TI  - Sirt3 Deletion Increases Inflammation and Mortality in Polymicrobial Sepsis.
PG  - 788-796
LID - 10.1089/sur.2023.161 [doi]
AB  - Background: Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide 
      (NAD)-dependent deacetylase that confers resilience to cellular stress by 
      promoting mitochondrial activity. Mitochondrial dysfunction is a major driver of 
      inflammation during sepsis. We hypothesize that Sirt3 expression improves 
      survival in polymicrobial sepsis by mitigating the inflammatory response. 
      Materials and Methods: Sirt3 knockout (S3KO) and wild-type (WT) mice underwent 
      cecal ligation and puncture (CLP) or sham surgery. mRNA expression was quantified 
      using quantitative polymerase chain reaction (qPCR) and protein expression was 
      quantified using enzyme-linked immunosorbent assay (ELISA). Spectrophotometric 
      assays were used to quantify serum markers of organ dysfunction. For in vitro 
      studies, bone marrow-derived macrophages (BMDMs) were harvested from S3KO and WT 
      mice and treated with lipopolysaccharide (LPS). Results: After CLP, hepatic Sirt3 
      levels decreased from baseline by nine hours and remained depressed at 24 hours. 
      Peak serum interleukin-6 (IL-6) protein levels were higher in S3KO mice. In 
      LPS-treated BMDMs, IL-6 mRNA levels peaked earlier in S3KO cells, although peak 
      levels were comparable to WT. Although S3KO mice had decreased median survival 
      after CLP compared with WT, there was no difference in five-day survival or organ 
      dysfunction. Conclusions: Although S3KO mice initially had increased inflammation 
      and mortality, this difference abated with time, and overall survival was 
      comparable between the groups. This pattern is consistent with the timeline of 
      sepsis-induced Sirt3 downregulation in WT mice, and suggests that Sirt3 
      downregulation occurring in sepsis is at least partially responsible for the 
      initial hyperinflammatory response and subsequent mortality. Our data support 
      upregulation of Sirt3 as a promising therapeutic strategy for further research in 
      sepsis.
FAU - Labiner, Hanna E
AU  - Labiner HE
AD  - Division of Trauma, Critical Care, and Burn at The Ohio State University Wexner 
      Medical Center, The Ohio State University, Columbus, Ohio, USA.
FAU - Sas, Kelli M
AU  - Sas KM
AD  - Division of Trauma, Critical Care, and Burn at The Ohio State University Wexner 
      Medical Center, The Ohio State University, Columbus, Ohio, USA.
FAU - Baur, Joseph A
AU  - Baur JA
AD  - Institute for Diabetes, Obesity and Metabolism and Department of Physiology, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania, USA.
FAU - Sims, Carrie A
AU  - Sims CA
AD  - Division of Trauma, Critical Care, and Burn at The Ohio State University Wexner 
      Medical Center, The Ohio State University, Columbus, Ohio, USA.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Surg Infect (Larchmt)
JT  - Surgical infections
JID - 9815642
RN  - 0 (Interleukin-6)
RN  - EC 3.5.1.- (Sirtuin 3)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sirt3 protein, mouse)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Interleukin-6
MH  - *Sirtuin 3/genetics/metabolism
MH  - Lipopolysaccharides
MH  - Multiple Organ Failure
MH  - Inflammation
MH  - *Sepsis/genetics/metabolism
MH  - Mice, Knockout
MH  - RNA, Messenger
MH  - Mice, Inbred C57BL
PMC - PMC10659016
OTO - NOTNLM
OT  - anti-inflammatory
OT  - dysregulated host response
OT  - mitochondrial activity
OT  - sirtuin
COIS- The authors have no conflicts of interest to disclose.
EDAT- 2023/11/28 18:42
MHDA- 2023/11/30 06:42
PMCR- 2024/11/01
CRDT- 2023/11/28 12:13
PHST- 2024/11/01 00:00 [pmc-release]
PHST- 2023/11/30 06:42 [medline]
PHST- 2023/11/28 18:42 [pubmed]
PHST- 2023/11/28 12:13 [entrez]
AID - 10.1089/sur.2023.161 [pii]
AID - 10.1089/sur.2023.161 [doi]
PST - ppublish
SO  - Surg Infect (Larchmt). 2023 Nov;24(9):788-796. doi: 10.1089/sur.2023.161.