Gene Expression of Heme Oxygenase-1: Relationship to Fibrogenic and Apoptotic Factors in Murine Schistosomiasis

Abstract

Schistosomiasis is characterized by a unique form of periportal fibrosis and not cirrhosis. Heme oxygenase (HO-1) is a stress inducible molecule that could modulate the fibrogenic process in the murine model of schistosoma mansoni. In this study, the extent of heme oxygenase-1 gene expression was evaluated by RT-PCR in liver tissues of thirty mice infested with schistosoma mansoni after the 2nd, 4th, 6th, 8th and 10th weeks of infestation. Furthermore, the gene expression of some fibrogenic and antifibrogenic factors [pro α₂ (I) collagen, laminin β1, transforming growth factor β (TGF-β), platelet derived growth factor (PDGF) and hepatocyte growth factor (HGF)], apoptotic factors (Fas L) and the transcriptional factor nuclear factor-κB (NF-κB) were also evaluated in liver tissues of the same animals by RT-PCR techniques. The PCR bands densities were semi-quantitated using Biometra gel documentation system. The present study showed that the gene expression of HO-1 coincided with the expression of NF-κB. Both were induced from the 2nd week post infestation and their PCR band density remained high till the 8th week with a slight decline at the 10th week. The gene expression of HO-1 paralleled the levels of HO activity. On the other hand, increase in gene expression of HGF and Fas L was detected only in the 2nd and the 4th weeks post infestation. This may suggest a down regulation of Fas L and HGF by the sustained increase in gene expression of HO-1 and/or NF-κB. Meanwhile, there is increase in the gene expression of the profibrogenic cytokines PDGF and TGF-β, starting in the 4th week (PDGF) and 6th week (TGF-β). They were however expressed at low levels at the 2nd and 4th weeks, respectively. Thus a direct effect of HO-1 on the expression of these cytokines cannot be sharply delineated. However, the expression of these cytokines preceded and then paralleled pro α₂ (1) collagen gene expression, indicating their role in the fibrogenic process. Laminin gene expression increased from the 6th week and remained highly expressed till the 10th weeks. Thus the similar patterns of gene expression of HO-1 and NF-κB at the selected stages in murine schistosomiasis and the accompanying down regulation of the Fas L suggest that, as a stress inducible protein, HO-1 might be part of the protective mechanisms elicited by the acute phase response in Schistosoma mansoni infection possibly by protecting the cells against the consequences of oxidative stress (i.e. apoptotic and necrotic pathways). HO-1 gene expression may play a role in the modulation of the immunopathology of schistosomiasis and hence, indirectly influence fibrogenesis and prevent cirrhosis.