Abstract
Acute rejection (AR) and spontaneous tolerance may occur after allograft orthotopic liver transplants (OLT) performed in certain combinations of donor and recipient rat strains, yet the underlying molecular cascades involved in these conditions remain poorly understood. Comprehensive analysis with proteomic tools revealed that ceruloplasmin was highly expressed during the tolerant period on day 63 post-OLT (POD 63) compared to the rejected samples on POD 14. Meanwhile, cytokine expression profiles implied that the inflammation was significantly stimulated in the AR subjects. Again, protein carbonylation was dramatically upregulated in the rejected subject within the tolerant group. Knockdown of ceruloplasmin would elicit more severe ROS damage, leading to cell death in the presence of H2O2, which induced Nrf2 cascade and the recovery of ceruloplasmin to mediate spontaneous tolerance. In summary, ceruloplasmin may contribute to amending the oxidative stress that eventually causes cell apoptosis and to maintaining the survival of hepatocytes in a drug-free tolerance OLT model.
Highlights
Orthotopic liver transplantation (OLT) has become a definitive therapeutic option in patients with acute or chronic liver disease while immune rejection is still a major cause of operation failure and mortality [1,2,3]
The results indicated that H2O2 obviously reduced the expression of ceruloplasmin compared to the control and activated the caspase-3 cascades leading to cell apoptosis
We have made efforts to set up the functional proteome for the certification of serum proteins that might be responsible for spontaneous tolerance of OLT in rats [39]
Summary
Orthotopic liver transplantation (OLT) has become a definitive therapeutic option in patients with acute or chronic liver disease while immune rejection is still a major cause of operation failure and mortality [1,2,3]. During different stages of liver allograft rejection or tolerance, huge numbers of immune cells, serum proteins, and molecules associated with immune responses will change in quantity and quality [9,10,11,12]. The functional “signature network” using MetaCoreTM pathway analysis tools produces overall cellular mechanisms derived from differences in protein and cytokine levels. This method simultaneously delineates the signaling pathways in view of the architecture to represent biological functionality and the integration of molecular and clinical information [23, 24]. Our findings may provide important information for therapeutic designs after transplantation and enhance survival rate by predicting disease progression as well as treatment responses
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