Abdel-Aziz, T.M.E.; (2012) Novel therapeutic strategies for prevention of postresectional liver failure. Doctoral thesis , UCL (University College London).

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Abstract

Background: Sinusoidal obstruction syndrome (SOS) occurs in 50-70% of patients receiving oxaliplatin for hepatic metastasis. Patients suffering from SOS preoperatively are at increased risk of developing postresectional liver failure. To date, there is no ideal therapy to prevent SOS. Moreover, SOS delays liver regeneration following liver resections instigating the possible role of cell therapy. It is essential however to understand the dynamics of the transplanted cells. First, we studied the effect of a flavonoid (monoHER) on prevention of SOS. Second, we studied the role of a dual labeling technique for non-invasive tracking of stem cells in-vivo. Methods: A monocrotaline (MCT) induced SOS model was used in rats, with/without monoHER pretreatment. We studied hepatocellular damage and matrix metalloproteinase (MMP) expression. The potential inhibition of oxaliplatin-induced cytotoxicity by monoHER was tested in-vitro. In the second experiment, liver damage was induced in mice by acetaminophen. Green fluorescence protein (GFP) positive mouse embryonic stem cells (ESCs) were stained with a near infrared dye before transplantation. The distribution of the cells was monitored real-time. Immunohistochemistry was used to identify expression of GFP and albumin. Results: MonoHER ameliorated the increase in portal pressure after MCT and prevented hepatocellular damage. The liver damage score was lower in the monoHER group and was associated with less inflammation. Livers of MCT-treated rats had higher expression of MMP-9 when compared to monoHER group. MonoHER had no effect on in-vitro proliferation of colorectal cancer cells. In the second experiment, labeled ESCs were easily tracked by non-invasive technique. Within 24-hr of transplantation, homing of almost 90% cells was confirmed in the liver. Constitutively expressed GFP was used to study the cell distribution. Conclusions: MonoHER prevented MCT induced portal hypertension and hepatic injury in rats. Dual labeling is an effective method for longitudinal monitoring of distribution, survival and engraftment of transplanted cells.

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