The disconnect between animal models of sepsis and human sepsis

University of Michigan, Ann Arbor, Michigan, United States
Journal of Leukocyte Biology (Impact Factor: 4.29). 02/2007; 81(1):137-43. DOI: 10.1189/jlb.0806542
Source: PubMed


Frequently used experimental models of sepsis include cecal ligation and puncture, ascending colon stent peritonitis, and the i.p. or i.v. injection of bacteria or bacterial products (such as LPS). Many of these models mimic the pathophysiology of human sepsis. However, identification of mediators in animals, the blockade of which has been protective, has not translated into clinical efficacy in septic humans. We describe the shortcomings of the animal models and reasons why effective therapy for human sepsis cannot be derived readily from promising findings in animal sepsis.

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    • "Therefore, determining the redistribution of T and NKT cell populations in various organs after sepsis will help us to understand the contribution of each compartment in affecting T and NKT cells. In the present study, we used a mouse model of sepsis induced by cecal ligation and puncture (CLP), which is the most widely used and physiologically relevant experimental model for the induction of polymicrobial sepsis [20]. We then measured and compared the frequency and total numbers of CD4 + and CD8 + T lymphocytes, various CD4 + T subsets including Tregs, and NKT cells in various lymphoid and non-lymphoid organs, including thymus, spleen, liver and lungs, as well as the blood in healthy and septic mice. "
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    • "Inhibiting RAGE decreased the levels of multiple pro-inflammatory mediators implicated in the pathophysiology of sepsis and improved short-term survival in rodent models of sepsis6,7. Clinical trials of interventions designed to modulate the immune response to acute insults and sepsis have been disappointing8,9; therefore, inhibition of the RAGE axis could provide another strategy for improving clinical outcome. However, it is unclear whether blockade of RAGE can influence the host immune response and survival secondary to severe burns in vivo. "
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    ABSTRACT: Aim: The receptor of advanced glycation end products (RAGE) participates in a variety of pathophysiological processes and inflammatory responses. The aim of this study was to investigate the therapeutic potential of an anti-RAGE neutralizing antibody for severe thermal injury in rats, and to determine whether the treatment worked via modulating cellular immune function. Methods: Full-thickness scald injury was induced in Wistar rats, which were treated with the anti-RAGE antibody (1 mg/kg, iv) at 6 h and 24 h after the injury. The rats were sacrificed on d 1, 3, 5, and 7. Blood and spleen samples were harvested to monitor organ function and to analyze dendritic cell (DC) and T cell cytokine profiles. The survival rate was analyzed up to d 7 after the injury. Results: Administration of the antibody significantly increased the 7 d survival rate in thermally injured rats (6.67% in the model group; 33.33% in anti-RAGE group). Treatment with the antibody also attenuated the multiple organ dysfunction syndrome (MODS) following the thermal injury, as shown by significant decreases in the organ dysfunction markers, including serum ALT, AST, blood urea nitrogen, creatinine and CK-MB. Moreover, treatment with the antibody significantly promoted DC maturation and T cell activation in the spleens of thermally injured rats. Conclusion: Blockade of the RAGE axis by the antibody effectively ameliorated MODS and improved the survival rate in thermally injured rats, which may be due to modulation of cellular immune function.
    Full-text · Article · Aug 2014 · Acta Pharmacologica Sinica
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    • "Unfortunately, the animal model of sepsis induced by LPS does not fully recapitulate the many facets of the septic shock response (Rittirsch et al., 2007). There is a need for animal models where the clinical signs of sepsis develop after exposure to endogenous bacterial pathogens. "
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    ABSTRACT: During bacterial sepsis, proinflammatory cytokines contribute to multiorgan failure and death in a process regulated in part by cytolytic cell granzymes. When challenged with a sublethal dose of the identified mouse pathogen Brucella microti, wild-type (WT) and granzyme A (gzmA)(-/-) mice eliminate the organism from liver and spleen in 2 or 3 weeks, whereas the bacteria persist in mice lacking perforin or granzyme B as well as in mice depleted of Tc cells. In comparison, after a fatal challenge, only gzmA(-/-) mice exhibit increased survival, which correlated with reduced proinflammatory cytokines. Depletion of natural killer (NK) cells protects WT mice from sepsis without influencing bacterial clearance and the transfer of WT, but not gzmA(-/-) NK, cells into gzmA(-/-) recipients restores the susceptibility to sepsis. Therefore, infection-related pathology, but not bacterial clearance, appears to require gzmA, suggesting the protease may be a therapeutic target for the prevention of bacterial sepsis without affecting immune control of the pathogen.
    Full-text · Article · Jul 2014 · Cell Reports
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