Animal Models of Sepsis Pathophysiology

Sepsis arises from a dysregulated host response to infection and leads to widespread organ dysfunction and high mortality. Animal models are indispensable for dissecting the complex interplay between pathogen invasion, innate immunity, vascular disturbance and organ injury. The most widely used approaches include administration of purified endotoxin such as lipopolysaccharide, surgical induction of polymicrobial peritonitis by cecal ligation and puncture (CLP), intraperitoneal injection of cecal slurry and chemically induced gut mucosal injury. Each model reproduces distinct aspects of human sepsis: endotoxaemia models acute systemic inflammation, CLP mimics perforated viscus and polymicrobial infection, and slurry injection offers a reproducible polymicrobial challenge. More recent refinements incorporate fluid resuscitation, antibiotic therapy and physiological monitoring to mirror critical care approaches. Detailed phenotyping of immune cell dynamics, metabolic shifts and microvascular function in these models has revealed how neutrophil recruitment, microRNA networks in epithelial barriers and emergency myelopoiesis influence outcomes. Despite persistent gaps in translational success, these experimental platforms remain crucial for evaluating novel therapeutics and elucidating fundamental mechanisms driving vascular leakage, coagulopathy and organ failure in sepsis.

Research from Nature Portfolio

A recent study has identified CD5L, a circulating immunomodulatory protein, as a promising therapeutic in experimental sepsis. In mice subjected to medium- or high-grade CLP, loss of CD5L impaired neutrophil recruitment, compromised bacterial clearance and amplified pro-inflammatory gene expression. Intravenous administration of recombinant CD5L restored neutrophil phagocytic function, reduced circulating endotoxin and damage-associated molecular patterns, and markedly improved survival in both CLP-induced sepsis and lipopolysaccharide-induced endotoxic shock models. These findings underscore the potential of targeting endogenous modulators of neutrophil activity to rebalance the immune response and limit organ damage in sepsis.

Animal Models of Sepsis Pathophysiology publication trend

The graph below shows the total number of articles in animal models of sepsis pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Cecal ligation and puncture (CLP): A surgical technique that induces polymicrobial peritonitis by tying off and perforating the caecum to mimic gut-derived sepsis.

Lipopolysaccharide (LPS): A component of Gram-negative bacterial outer membranes used experimentally to provoke systemic inflammation and endotoxaemia.

Damage-associated molecular patterns (DAMPs): Host-derived molecules released from injured cells that amplify sterile and infectious inflammation.

Polymicrobial sepsis: A model of sepsis involving multiple bacterial species, replicating the complex microbial milieu of human intra-abdominal infections.

MicroRNA (miRNA): Small non-coding RNAs that regulate gene expression post-transcriptionally, shaping inflammatory and repair pathways in sepsis.

References

1. CD5L as a promising biological therapeutic for treating sepsis. Nature Communications (2024).
2. Protective Effect of Pentoxifylline on the Development of Acute Gastric Mucosal Injury in a Model of LPS-Induced Sepsis. Antioxidants (2024).
3. MicroRNA Profiles in Intestinal Epithelial Cells in a Mouse Model of Sepsis. Cells (2023).
4. Comprehensive comparison of three different animal models for systemic inflammation. Journal of Biomedical Science (2017).
5. A New Cecal Slurry Preparation Protocol with Improved Long-Term Reproducibility for Animal Models of Sepsis. PLOS ONE (2014).
6. Preclinical septic shock research: why we need an animal ICU. Annals of Intensive Care (2019).