The disconnect between animal models of sepsis and human sepsis

University of Michigan, Ann Arbor, Michigan, United States
Journal of Leukocyte Biology (Impact Factor: 4.3). 02/2007; 81(1):137-43. DOI: 10.1189/jlb.0806542
Source: PubMed

ABSTRACT 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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    • "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.
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    • "In contrast, oxidants generated by the NADPH oxidase suffice in responding effectively to challenges with low inocula (Aratani et al., 2002a,b). Although the validity of extrapolations from MPO knock-out mice to humans can be undermined by inherent differences between phagocytes from the two species with respect to NADPH oxidase activity, MPO content and the repertoire of MPOindependent antimicrobial agents such as defensins (Rausch and Moore, 1975; Eisenhauer and Lehrer, 1992; Mestas and Hughes, 2004; Rittirsch et al., 2007), the contributions of MPO to the inflammatory process per se, independent of direct antimicrobial action, also obfuscate interpretation of the results of experimental models. MPO knock-out animals express higher levels of induced nitric oxide synthase, generate more nitric oxide, and exhibit less lung injury in response to sepsis or endotoxin (Brovkovych et al., 2008; Haegens et al., 2009; Takeuchi et al., 2012), demonstrating that overall survival from infection reflects important factors in addition to the eradication of viable organisms. "
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    ABSTRACT: Human neutrophils represent the predominant leucocyte in circulation and the first responder to infection. Concurrent with ingestion of microorganisms, neutrophils activate and assemble the NADPH oxidase at the phagosome, thereby generating superoxide anion and hydrogen peroxide. Concomitantly, granules release their contents into the phagosome, where the antimicrobial proteins and enzymes synergize with oxidants to create an environment toxic to the captured microbe. The most rapid and complete antimicrobial action by human neutrophils against many organisms relies on the combined efforts of the azurophilic granule protein myeloperoxidase and hydrogen peroxide from the NADPH oxidase to oxidize chloride, thereby generating hypochlorous acid and a host of downstream reaction products. Although individual components of the neutrophil antimicrobial response exhibit specific activities in isolation, the situation in the environment of the phagosome is far more complicated, a consequence of multiple and complex interactions among oxidants, proteins and their by‐products. In most cases, the cooperative interactions among the phagosomal contents, both from the host and the microbe, culminate in loss of viability of the ingested organism.
    Cellular Microbiology 05/2014; DOI:10.1111/cmi.12312 · 4.82 Impact Factor
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    • "The correct diagnosis and treatment of sepsis is complicated, but it must be fast, since the delayed approach raises the risk of death [3]. Bacterial endotoxin or lipopolysaccharide (LPS) is a major component of the cell walls of gram-negative bacteria and experimentally mimics a number of physiological responses in animal models of sepsis [4]. Oxidative stress and inflammation [e.g. "
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    ABSTRACT: Sepsis is a leading cause of death in intensive care units worldwide. Low availability of glutamine contributes to the catabolic state of sepsis. l-Glutamine supplementation has antioxidant properties and modulates the expression of heat shock proteins (HSPs). This study investigated the effects of oral supplementation with l-glutamine plus l-alanine (GLN+ALA), both in the free form and l-alanyl-l-glutamine dipeptide (DIP), on glutamine-glutathione (GSH) axis and HSPs expression in endotoxemic mice. B6.129F2/J mice were subjected to endotoxemia (lipopolysaccharides from Escherichia coli, 5, LPS group) and orally supplemented for 48 h with either l-glutamine (1 plusl-alanine (0.61 (GLN+ALA-LPS group) or 1.49 of DIP (DIP-LPS group). Endotoxemia reduced plasma and muscle glutamine concentrations [relative to CTRL group] which were restored in both GLN+ALA-LPS and DIP-LPS groups (P<.05). In supplemented groups were re-established GSH content and intracellular redox status (GSSG/GSH ratio) in circulating erythrocytes and muscle. Thiobarbituric acid reactive substance was 4-fold in LPS treated mice relative to the untreated CTRL group, and plasma TNF-α and IL-1β levels were attenuated by the supplements. Heat shock proteins 27, 70 and 90 (protein and mRNA) were elevated in the LPS group and were returned to basal levels (relative to CTRL group) in both GLN+ALA-LPS and DIP-LPS groups. Supplementations to endotoxemic mice resulted in up-regulation of GSH reductase, GSH peroxidase and glutamate cysteine ligase mRNA expression in muscle. In conclusion, oral supplementations with GLN+ALA or DIP are effective in reversing the conditions of LPS-induced deleterious impact on glutamine-GSH axis in mice under endotoxemia.
    The Journal of nutritional biochemistry 03/2014; 25(3):345-52. DOI:10.1016/j.jnutbio.2013.11.009 · 4.59 Impact Factor
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