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Development and characterization of a rat model of nonpenetrating liver trauma.

ABSTRACT: The aim of this study was to develop and characterize a rodent model of liver trauma suitable for preclinical evaluation of new treatments and diagnostic technologies. Liver trauma was created by dropping a steel cylinder through a plastic tube onto the abdomen of supine, anesthetized rats. Internal hemorrhage in the absence of liver trauma was simulated by instilling fresh blood into the peritoneum. Platelet counts were elevated significantly after liver trauma but not simulated hemorrhage. Liver trauma and simulated internal hemorrhage both increased blood levels of the factor growth-regulated oncogene-Kupffer cell. Transcription of plasminogen activator inhibitor 1, heat shock protein 70, and suppressor of cytokine syntheses 3 was increased 77-, 22-, and 27-fold, respectively, 2 h after liver trauma but was unaltered by simulated internal hemorrhage. Levels returned to pretrauma levels by 24 h after trauma. Transcript levels for hypoxia-inducible transcription factor 1alpha were increased 2.8-fold at 24 h but not 2 h after trauma and were not affected by simulated hemorrhage. Production of heat shock protein 70 and inducible nitric oxide synthase in liver was limited to a penumbra surrounding areas of necrosis associated with trauma. The rat model described produces lesions similar to those that occur in humans after blunt trauma.

SUBMITTER: Cox JM

PROVIDER: S-EPMC2890397 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Development and characterization of a rat model of nonpenetrating liver trauma.

Cox Jennifer M JM Kalns John E JE

Comparative medicine 20100601 3

The aim of this study was to develop and characterize a rodent model of liver trauma suitable for preclinical evaluation of new treatments and diagnostic technologies. Liver trauma was created by dropping a steel cylinder through a plastic tube onto the abdomen of supine, anesthetized rats. Internal hemorrhage in the absence of liver trauma was simulated by instilling fresh blood into the peritoneum. Platelet counts were elevated significantly after liver trauma but not simulated hemorrhage. Liv ...[more]

PMID: 20579437

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Project description:Precision-cut liver tissue slice (PCLS) contains all major cell types of the liver parenchyma and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study liver fibrosis and test the antifibrotic effect of experimental compounds in a physiological environment. In this study using RNA sequencing, we demonstrated that various pathways functionally related to fibrotic mechanisms were dysregulated in PCLSs derived from rats subjected to bile duct ligation. The activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib each reversed a subset of genes dysregulated in fibrotic PCLSs, and of those genes we identified 608 genes whose expression was reversed by all three compounds. These genes define a molecular signature characterizing many aspects of liver fibrosis pathology and its attenuation in the model. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were further validated as efficacy end points for the evaluation of antifibrotic activity of experimental compounds. Finally, we showed that blockade of ?V-integrins with a small molecule inhibitor attenuated the fibrotic phenotype in the model. Overall, our results suggest that the rat fibrotic PCLS model may represent a valuable system for target validation and determining the efficacy of experimental compounds. NEW & NOTEWORTHY We investigated the antifibrotic activity of three compounds, the activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib, in a rat fibrotic precision-cut liver tissue slice model using RNA sequencing analysis. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were then established as efficacy end points to validate the antifibrotic activity of the ?V-integrin inhibitor CWHM12. This study demonstrated the value of the rat fibrotic PCLS model for the evaluation of antifibrotic drugs.

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Development and characterization of a rat model of nonpenetrating liver trauma.

Publications

Development and characterization of a rat model of nonpenetrating liver trauma.

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