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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    ABSTRACT: Among immune cells in responding to sepsis, macrophages and neutrophils have been extensively studied, while the contribution of T lymphocytes and natural killer T (NKT) cells is less well characterized. Here we monitored tissue specific changes of T cell subsets in male C57BL/6 mice subjected to sham operation or cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Thymus, spleen, liver, lungs and blood were processed and analyzed 20h later. Total lymphocyte count showed a significant reduction in septic thymus, spleen and blood but not in lungs and liver. The septic thymi were hypocellular with severe reduction in cell numbers of immature CD4(+)CD8(+) subset. CD4(+) T and CD8(+) T lymphocyte numbers in septic spleens were also significantly reduced, but the frequency of CD4(+)CD25(+) Tregs was significantly increased. In addition, naïve and Tcm CD4(+) T cell numbers were significantly reduced in the septic spleens. By contrast, in septic liver the CD8(+) T cell numbers were significantly increased, whereas NKT cell numbers were reduced, but more activated with increased CD69 and CD25 expression. In the septic lungs, the CD4(+) T and CD8(+) T cell numbers showed no significant change, whereas they were severely reduced in the septic blood. Overall, this study provides important information on the alterations of different T-cell subsets in various tissues after sepsis.
    Immunology letters 09/2015; DOI:10.1016/j.imlet.2015.09.005 · 2.51 Impact Factor
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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.
    Acta Pharmacologica Sinica 08/2014; 35(9). DOI:10.1038/aps.2014.56 · 2.91 Impact Factor
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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.
    Cell Reports 07/2014; 8(2). DOI:10.1016/j.celrep.2014.06.012 · 8.36 Impact Factor
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