Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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We investigated the effects of a protein-bound polysaccharide, PSK, on the resistance of tumor-bearing mice against sepsis induced by cecal ligation and puncture (CLP). (a) In BALB/c mice that had received intracecal transplantation of colon 26 (C26) tumor, CLP with a 21-gauge needle significantly shortened the survival time, compared with that of non-tumor-bearing mice. Oral administration of PSK to such mice resulted in a significant prolongation of the survival time and increase of the survival rates. ⋯ Further, PSK prevented the reduction of gene expression of IFN-gamma and the number of IFN-gamma-producing CD4-positive T cells and IFN-gamma productivity by spleen cells of tumor-bearing CLP-treated mice. (c) Treatment with anti-IFN-gamma monoclonal antibody before CLP significantly reduced the effects of PSK. These findings suggest that the protective effect of PSK on the CLP-induced sepsis in mice transplanted orthotopically with C26 tumor is possibly mediated by suppression of IL-10 and promotion of IFN-gamma.
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The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. ⋯ There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design and reporting of studies of preclinical models of acute illness precludes more sophisticated data synthesis.
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A few limited examples of large animal models are outlined, with the main emphasis on baboon models. The baboon offers all the advantages of a large animal and is comparable with humans in nearly all physiological and immunological aspects. In addition, cross-reactivity with human therapeutic and diagnostic reagents allows testing of new species-specific therapies such as antihuman antibodies, on the one hand, and monitoring with available human analytical procedures, on the other.
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Many strategies have been proposed for the treatment of sepsis, and most of the proposed treatment modalities have failed in clinical trials. Many of the previous treatment protocols called for blocking the activity of a single, clearly defined mediator. The underlying hypothesis was that sepsis induced a specific mediator that then caused organ injury and death. ⋯ The cytokine response in focus of infection models, such as that induced by cecal ligation and puncture, was examined and found to be more similar to that observed in patients with sepsis. When cytokine inhibitor strategies were used in the cecal ligation and puncture model, they were also generally found to lack efficacy. Compounds that have been shown to be effective at reducing mortality in endotoxin models should be re-evaluated in more clinically relevant models of sepsis.
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The goal of translational research is to transform biologic knowledge into new treatments for human disease. Although preclinical models replicate some of the features of the disease process modeled, they invariably fail to reproduce the complexity of human illness, and by their very experimental nature, they are readily manipulated to maximize evidence of efficacy. The result is that successful translation from preclinical models to clinically effective therapy is uncommon, and that clinical trials are often undertaken without a comprehensive and realistic preclinical portfolio of studies to optimize their design. ⋯ A corollary of this conclusion is that preclinical studies can shape concepts of disease and can be used to refine decisions regarding optimal patient populations for therapeutic interventional trials. We further recognized that the design and reporting of preclinical studies is highly variable, thereby limiting effective data interpretation and integration between studies. Hence, greater model standardization would aid in interpreting data and in pooling results into systematic data syntheses: such efforts should be promoted and undertaken.