Liver resection is the most common surgical procedure performed on the liver, mostly for removal of malignant tumors. Ischemia and reperfusion injury (IRI) is unavoidable in the vast majority of liver resections performed. Failure of the liver to regenerate is a primary reason for post-surgical liver failure. The complement system has a dual role in liver recovery following resection in that it plays a key role in causing hepatic injury following ischemia and reperfusion, but also play an important role in the regenerative response. It is known that early complement activation products (C3a and C5a) are important for stimulating regeneration, but less is known about the role of C3a and C5a in IRI, or the role of the late complement activation product known as the membrane attack complex (MAC) in IRI and regeneration. Furthermore, it is not clear how complement is activated following hepatic ischemia and reperfusion (IR) or liver resection. The goals of this project are to understand the proximal events involved in complement activation following IR or hepatectomy, and to characterize differences in complement effector mechanisms involved in IRI and regeneration. Based on data obtained, a further goal is to develop and characterize a therapeutic approach to inhibit complement that will prevent IRI without adversely effecting (or even promoting) regeneration.
The specific aims of this project are to: 1) Determine the role of naturally occurring self reactive IgM in activating complement following IR and regeneration. Preliminary data indicate that complement is activated by IgM bound to neoeptipes that become exposed following IR or partial hepatectomy. Neoepitope expression and IgM binding will be quantitatively and qualitatively characterized using a panel of recently isolated self reactive IgM monoclonal antibodies. 2) Determine the role of the terminal complement pathway in liver IRI and regeneration. To define the role of the MAC in IRI, and to investigate whether it contributes to injury/regeneration following partial hepatectomy, we will determine the effect of C6 deficiency (blocked in terminal complement pathway) on inflammation, injury and regenerative response in IRI and partial hepatectomy models. 3) Investigate complement inhibitory strategies based on minimizing liver IRI and promoting regeneration. A novel strategy of targeting complement inhibition will be investigated in a clinically relevant model that combines IRI and partial hepatectomy. The strategy will be based in part on data from aim 1 and will involve a complement inhibitor specific for the terminal pathway that is targeted to neoepitopes exposed after surgery.
Relevence Failure of the liver to regenerate is a major reason for post-surgical liver failure. Developing a therapy that would decrease injury of the liver and improve regeneration following surgery would greatly impact morbidity and patient recovery. Furthermore, on a global scale, insight into the mechanism of complement in liver injury and regeneration could potentially be applied to other disease states such as stroke, heart disease, autoimmune diseases and many other inflammatory conditions.