Introduction Sinusoidal obstruction syndrome (SOS) following Oxaliplatin based chemotherapy is a cause for major concern when undertaking liver resection for colorectal liver metastases. To date no relevant experimental models of Oxaliplatin induced SOS have been described. The aim of this project was to establish such a model which could be utilised to identify potential therapeutic strategies to prevent the development of SOS.
Methods C57Bl/6 mice were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for 5 weeks and culled 1 week following final treatment. Representative biopsies of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. RNA and protein were extracted from snap frozen biopsies of the liver and subject to biochemical, analysis by qRT-PCR and western blot respectively, for markers of matrix remodelling, vascular dysfunction/endothelial damage, DNA damage and cellular proliferation. Serum was separated from whole blood and markers of liver injury (ie, ALT, AST and Alk Phos) were also measured. Statistical significance was assessed with Mann–Whitney U Test.
Results FOLFOX treatment was associated with the development of sinusoidal dilatation and peri-venular hepatocyte atrophy on H&E stained sections of the liver in keeping with SOS. This was associated with an elevated serum ALT and AST (p<0.05). Immunohistochemistry for γH2AX demonstrated the presence of DNA damage in the sinusoidal endothelium. In the liver of FOLFOX treated animals there was up-regulation of key genes associated with matrix remodelling such as MMP9 (p<0.001), MMP2 (p<0.001), Pro-Collagen I (p<0.001) and TGFβ (p<0.001). There was evidence of endothelial damage and a subsequent pro-thrombotic state with up-regulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001).
Conclusion We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease process in patients. Through analysis of this model we have gained insights into the molecular changes that underpin the development of SOS and are now able to test potential therapeutic strategies to prevent it.
Competing interests None declared.