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Old Mice Demonstrate Organ Dysfunction as well as Prolonged Inflammation, Immunosuppression, and Weight Loss in a
Julie A Stortz1, McKenzie K Hollen1, Dina C Nacionales1
1Department of Surgery, University of Florida College of Medicine, Gainesville, FL.
Objectives:
Our goal was to "reverse translate" the human response to surgical sepsis into the mouse by modifying a widely adopted murine intra-abdominal sepsis model to engender a phenotype that conforms to current sepsis definitions and follows the most recent expert recommendations for animal preclinical sepsis research. Furthermore, we aimed to create a model that allows the study of aging on the long-term host response to sepsis.
Design:
Experimental study.
Setting:
Research laboratory.
Subjects:
Young (3-5 mo) and old (18-22 mo) C57BL/6j mice.
Interventions:
Mice received no intervention or were subjected to polymicrobial sepsis with cecal ligation and puncture followed by fluid resuscitation, analgesia, and antibiotics. Subsets of mice received daily chronic stress after cecal ligation and puncture for 14 days. Additionally, modifications were made to ensure that "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" recommendations were followed.
Measurements And Main Results:
Old mice exhibited increased mortality following both cecal ligation and puncture and cecal ligation and puncture + daily chronic stress when compared with young mice. Old mice developed marked hepatic and/or renal dysfunction, supported by elevations in plasma aspartate aminotransferase, blood urea nitrogen, and creatinine, 8 and 24 hours following cecal ligation and puncture. Similar to human sepsis, old mice demonstrated low-grade systemic inflammation 14 days after cecal ligation and puncture + daily chronic stress and evidence of immunosuppression, as determined by increased serum concentrations of multiple pro- and anti-inflammatory cytokines and chemokines when compared with young septic mice. In addition, old mice demonstrated expansion of myeloid-derived suppressor cell populations and sustained weight loss following cecal ligation and puncture + daily chronic stress, again similar to the human condition.
Conclusions:
The results indicate that this murine cecal ligation and puncture + daily chronic stress model of surgical sepsis in old mice adhered to current Minimum Quality Threshold in Pre-Clinical Sepsis Studies guidelines and met Sepsis-3 criteria. In addition, it effectively created a state of persistent inflammation, immunosuppression, and weight loss, thought to be a key aspect of chronic sepsis pathobiology and increasingly more prevalent after human sepsis.
Insights
This study developed a mouse model of surgical sepsis that mimics human sepsis, particularly in older individuals. The model demonstrates increased mortality, organ dysfunction, and chronic inflammation in aged mice, aligning with current research standards.
Area of Science:
- Immunology
- Gerontology
- Surgical Pathology
Background:
- Current sepsis research models require refinement to align with human disease phenotypes and current guidelines.
- Aging significantly impacts host response to sepsis, necessitating models that incorporate age-related changes.
Purpose of the Study:
- To "reverse translate" human sepsis into a murine model, adhering to "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" guidelines.
- To develop a model that allows investigation of aging's effects on the long-term host response to sepsis.
Main Methods:
- A polymicrobial sepsis model using cecal ligation and puncture (CLP) was modified in young and old C57BL/6j mice.
- Mice underwent CLP followed by resuscitation, analgesia, and antibiotics, with some experiencing daily chronic stress for 14 days.
- The model was adapted to meet Sepsis-3 criteria and "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" recommendations.
Main Results:
- Old mice exhibited higher mortality and significant hepatic/renal dysfunction post-CLP compared to young mice.
- Aged mice showed persistent low-grade inflammation, immunosuppression, and weight loss 14 days after CLP and chronic stress.
- Expansion of myeloid-derived suppressor cells was observed in old mice, mirroring human sepsis conditions.
Conclusions:
- The modified murine CLP model with chronic stress in old mice aligns with current sepsis research quality standards and Sepsis-3 criteria.
- This model effectively replicates chronic sepsis pathobiology, including persistent inflammation and immunosuppression, relevant to human aging and sepsis.
- The model provides a valuable platform for studying the long-term consequences of sepsis in aging populations.
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