Apoptosis in liver during malaria: role of oxidative stress and implication of mitochondrial pathway.
Hepatic dysfunction is a common clinical complication in malaria, although its pathogenesis remains largely unknown. Using a variety of in vivo and ex vivo approaches, we have shown for the first time that malarial infection induces hepatic apoptosis through augmentation of oxidative stress. Apoptosis in hepatocyte has been confirmed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin-nick-end labeling assay (TUNEL) and caspase-3 activation. Gene expression analysis using RT-PCR indicates the significant down-regulation of Bcl-2 and up-regulation of Bax expression in liver of malaria infected mice suggesting the involvement of mitochondrial pathway of apoptosis. The levels of Fas expression and caspase-8 activity in infected liver were same as that of uninfected control mice indicating death receptor (Fas) pathway did not contribute to liver apoptosis during malarial infection. Moreover, evidence has been presented by confocal microscopy to show the translocation of Bax from cytosol to mitochondria in apoptotic hepatocyte, resulting in opening of permeability transition pores, which in turn decreases mitochondrial membrane potential and induces cytochrome c release into cytosol. Malarial infection induces the generation of hydroxyl radical (*OH) in liver, which may be responsible for the induction of oxidative stress and apoptosis as administration of *OH specific antioxidant as well as spin trap, alpha-phenyl-tert-butyl-nitrone in malaria-infected mice significantly inhibits the development of oxidative stress as well as induction of apoptosis. Thus, results suggest the implication of oxidative stress induced-mitochondrial pathway of apoptosis in the pathophysiology of hepatic dysfunction in malaria.
Guha
Mithu
M
Division of Drug Target Discovery and Development, Central Drug Research Institute, Chatter Manzil Palace, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India.
Kumar
Sanjay
S
Choubey
Vinay
V
Maity
Pallab
P
Bandyopadhyay
Uday
U
D000818:Animals; D017209:Apoptosis; D022781:Hepatocytes / Q000473:pathology; D017665:Hydroxyl Radical / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008288:Malaria / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D018384:Oxidative Stress; D010967:Plasmodium yoelii
D017665:Hydroxyl Radical