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In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice.

ABSTRACT: The inflammatory phenotype of genetically modified mice is complex, and the role of Gram-negative lipopolysaccharide (LPS) in acute inflammation induced by surgical cannulation trauma, alone or in combination with hemorrhage and resuscitation ("hemorrhagic shock"), is both complex and controversial. We sought to determine if a mathematical model of acute inflammation could elucidate both the phenotype of CD14-deficient (CD14(-/-)) mice--following LPS, cannulation, or hemorrhagic shock--and the role of LPS in trauma/hemorrhage-induced inflammation. A mathematical model of inflammation initially calibrated in wild-type (C57Bl/6) mice subjected to LPS, cannulation, and hemorrhagic shock was recalibrated in CD14(-/-) mice subjected to the same insults, yielding an ensemble of models that suggested specific differences at the cellular and molecular levels (for example, 43-fold lower activation of leukocytes by LPS). The CD14(-/-)-specific model ensemble could account for complex changes in inflammatory analytes in these mice following LPS treatment. Model prediction of similar organ damage in CD14(-/-) and wild-type mice subjected to cannulation alone or with hemorrhagic shock was verified in vivo (similar ALT levels). These studies suggest that LPS-CD14 responses do not cause inflammation in surgical trauma/hemorrhagic shock and demonstrate a novel use of combined in silico and in vivo methods to elucidate the complex inflammatory phenotype of genetically modified animals.

SUBMITTER: Prince JM

PROVIDER: S-EPMC1578765 | biostudies-literature | 2006 Apr-Jun

REPOSITORIES: biostudies-literature

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In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice.

Prince Jose M JM Levy Ryan M RM Bartels John J Baratt Arie A Kane John M JM Lagoa Claudio C Rubin Jonathan J Day Judy J Wei Joyce J Fink Mitchell P MP Goyert Sanna M SM Clermont Gilles G Billiar Timothy R TR Vodovotz Yoram Y

Molecular medicine (Cambridge, Mass.) 20060401 4-6

The inflammatory phenotype of genetically modified mice is complex, and the role of Gram-negative lipopolysaccharide (LPS) in acute inflammation induced by surgical cannulation trauma, alone or in combination with hemorrhage and resuscitation ("hemorrhagic shock"), is both complex and controversial. We sought to determine if a mathematical model of acute inflammation could elucidate both the phenotype of CD14-deficient (CD14(-/-)) mice--following LPS, cannulation, or hemorrhagic shock--and the r ...[more]

PMID: 16953560

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Project description:Arsenic (As) is a toxic metalloid and human carcinogen that may cause hepatotoxicity. Fisetin (3, 3', 4', 7-tetrahydroxyflavone) is a phytoflavonoid, which shows diverse therapeutic activities. This study aimed to examine the remedial potential of fisetin against As-instigated hepatotoxicity in adult male rats. To accomplish this aim, albino rats (N = 48) were evenly classified into 4 groups: control group, As (10 mg/kg) group, fisetin (2.5 mg/kg) + As (10 mg/kg) group, and fisetin (2.5 mg/kg) group. After one month of treatment, biochemical assay, total protein content (TPC), hepatic serum enzymes, inflammatory as well as pro- or anti-apoptotic markers, and histopathological profile of hepatic tissues were estimated. As administration disordered the biochemical profile by decreasing activities of antioxidant enzymes i.e., catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSR), and glutathione (GSH) content while escalating the levels of reactive oxygen species (ROS), and thiobarbituric acid reactive substances (TBARS). TPC was also considerably reduced after exposure to As. Furthermore, As markedly raised the levels of liver serum enzymes such as aspartate transaminase (AST), alkaline phosphatase (ALP), and alanine transaminase (ALT) as well as the levels of inflammatory markers, i.e., nuclear factor- κB (NF-κB), tumor necrosis- α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclo-oxygenase-2 (COX-2) activity. Besides, it lowered the level of antiapoptotic markers (Bcl-2) and upregulated the levels of proapoptotic markers (Bax, Caspase-3, and Caspase-9). Additionally, As exposure led to histopathological damage in hepatic tissues. However, fisetin administration remarkably alleviated all the depicted hepatic damages. For further verification, the screening of several dock complexes was performed by using the GOLD 5.3.0 version. Based on docking fitness and GOLD score, the ranking order of receptor proteins with fisetin compound is superoxide dismutase, interleukin, aspartate aminotransferase, alkaline phosphatase, TNF-alpha, alanine transaminase, cyclo-oxygenase 2, antiapoptotic, and glutathione reductase. Out of these three receptor proteins superoxide dismutase, interleukin, and aspartate aminotransferase showed the best interaction with the fisetin compound. In vivo and in silico outcomes of the current study demonstrated that fisetin could potentially ameliorate As-instigated hepatotoxicity.

Dataset Information

In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice.

Publications

In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice.

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