Impact of age on the host response to sepsis in a murine model of fecal-induced peritonitis

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dc.contributor.authorSharma, Neha
dc.contributor.authorChen, Alex
dc.contributor.authorHeinen, Leah
dc.contributor.authorLiu, Ruth
dc.contributor.authorDwivedi, Dhruva J.
dc.contributor.authorZhou, Ji
dc.contributor.authorLalu, Manoj M.
dc.contributor.authorMendelson, Asher A.
dc.contributor.authorMcDonald, Braedon
dc.contributor.authorKretz, Colin A.
dc.contributor.authorFox-Robichaud, Alison E.
dc.contributor.authorLiaw, Patricia C.
dc.date.accessioned2024-04-01T16:25:51Z
dc.date.available2024-04-01T16:25:51Z
dc.date.issued2024-03-08
dc.date.updated2024-04-01T06:26:58Z
dc.description.abstractIntroduction Despite older adults being more vulnerable to sepsis, most preclinical research on sepsis has been conducted using young animals. This results in decreased scientific validity since age is an independent predictor of poor outcome. In this study, we explored the impact of aging on the host response to sepsis using the fecal-induced peritonitis (FIP) model developed by the National Preclinical Sepsis Platform (NPSP). Methods C57BL/6 mice (3 or 12 months old) were injected intraperitoneally with rat fecal slurry (0.75 mg/g) or a control vehicle. To investigate the early stage of sepsis, mice were culled at 4 h, 8 h, or 12 h to investigate disease severity, immunothrombosis biomarkers, and organ injury. Mice received buprenorphine at 4 h post-FIP. A separate cohort of FIP mice were studied for 72 h (with buprenorphine given at 4 h, 12 h, and then every 12 h post-FIP and antibiotics/fluids starting at 12 h post-FIP). Organs were harvested, plasma levels of Interleukin (IL)-6, IL-10, monocyte chemoattract protein (MCP-1)/CCL2, thrombin-antithrombin (TAT) complexes, cell-free DNA (CFDNA), and ADAMTS13 activity were quantified, and bacterial loads were measured. Results In the 12 h time course study, aged FIP mice demonstrated increased inflammation and injury to the lungs compared to young FIP mice. In the 72 h study, aged FIP mice exhibited a higher mortality rate (89%) compared to young FIP mice (42%) (p < 0.001). Aged FIP non-survivors also exhibited a trend towards elevated IL-6, TAT, CFDNA, CCL2, and decreased IL-10, and impaired bacterial clearance compared to young FIP non-survivors. Conclusion To our knowledge, this is the first study to investigate the impact of age on survival using the FIP model of sepsis. Our model includes clinically-relevant supportive therapies and inclusion of both sexes. The higher mortality rate in aged mice may reflect increased inflammation and worsened organ injury in the early stage of sepsis. We also observed trends in impaired bacterial clearance, increase in IL-6, TAT, CFDNA, CCL2, and decreased IL-10 and ADAMTS13 activity in aged septic non-survivors compared to young septic non-survivors. Our aging model may help to increase the scientific validity of preclinical research and may be useful for identifying mechanisms of age-related susceptibility to sepsis as well as age-specific treatment strategies.
dc.identifier.citationIntensive Care Medicine Experimental. 2024 Mar 08;12(1):28
dc.identifier.doi10.1186/s40635-024-00609-8
dc.identifier.urihttp://hdl.handle.net/1993/38116
dc.language.isoeng
dc.language.rfc3066en
dc.publisherSpringer Open
dc.rightsopen accessen_US
dc.rights.holderThe Author(s)
dc.subjectSepsis
dc.subjectAge
dc.subjectFecal‑induced peritonitis model
dc.subjectImmunothrombosis
dc.subjectNational Preclinical Sepsis Platform
dc.titleImpact of age on the host response to sepsis in a murine model of fecal-induced peritonitis
dc.typeJournal Article
local.author.affiliationRady Faculty of Health Science::Max Rady College of Medicine::Department of Internal Medicine
oaire.citation.issue28
oaire.citation.titleIntensive Care Medicine Experimental
oaire.citation.volume12
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