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

Autor: Sharma N; Thrombosis and Atherosclerosis Research Institute (TaARI), 237 Barton St E., Room C5-107, Hamilton, ON, L8L 2X2, Canada.; Department of Medical Sciences, McMaster University, Hamilton, ON, Canada., Chen A; McMaster University, Hamilton, ON, Canada., Heinen L; McMaster University, Hamilton, ON, Canada., Liu R; McMaster University, Hamilton, ON, Canada., Dwivedi DJ; Thrombosis and Atherosclerosis Research Institute (TaARI), 237 Barton St E., Room C5-107, Hamilton, ON, L8L 2X2, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Zhou J; Thrombosis and Atherosclerosis Research Institute (TaARI), 237 Barton St E., Room C5-107, Hamilton, ON, L8L 2X2, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Lalu MM; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Clinical Epidemiology Program, Blueprint Translational Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada.; Department of Anesthesiology and Pain Medicine, Department of Cellular and Molecular Medicine, The Ottawa Hospital, Ottawa, ON, Canada., Mendelson AA; Section of Critical Care Medicine, Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada., McDonald B; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Kretz CA; Thrombosis and Atherosclerosis Research Institute (TaARI), 237 Barton St E., Room C5-107, Hamilton, ON, L8L 2X2, Canada.; Department of Medical Sciences, McMaster University, Hamilton, ON, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Fox-Robichaud AE; Thrombosis and Atherosclerosis Research Institute (TaARI), 237 Barton St E., Room C5-107, Hamilton, ON, L8L 2X2, Canada.; Department of Medicine, McMaster University, Hamilton, ON, Canada., Liaw PC; Thrombosis and Atherosclerosis Research Institute (TaARI), 237 Barton St E., Room C5-107, Hamilton, ON, L8L 2X2, Canada. patricia.liaw@taari.ca.; Department of Medicine, McMaster University, Hamilton, ON, Canada. patricia.liaw@taari.ca.
Jazyk: angličtina
Zdroj: Intensive care medicine experimental [Intensive Care Med Exp] 2024 Mar 08; Vol. 12 (1), pp. 28. Date of Electronic Publication: 2024 Mar 08.
DOI: 10.1186/s40635-024-00609-8
Abstrakt: Introduction: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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