Therapeutic potential of complement inhibitors in myocardial ischaemia

Abstract

Under normal conditions, the complement system functions to eradicate microbes and other membrane bound pathogens. In other situations, complement activation comprises a pivotal mechanism for mediating tissue demolition in inflammatory disorders, including ischaemia/reperfusion injury. Complement-mediated tissue damage has long been recognised as a significant contributor to myocardial reperfusion injury. However, clinical use of complement inhibitors to reduce the extent of irreversible tissue injury related to reperfusion, remains in the early stages of development. Activation of the complement system generates anaphylatoxins, opsonins and the lytic moiety known as the membrane attack complex (MAC). In addition, fragments of the complement cascade proteins (e.g., C3a and C5a) secondarily initiate processes deleterious to myocytes by recruiting and stimulating inflammatory cells, such as neutrophils and macrophages, within the area of reperfusion. Damaged tissue itself, is capable of upregulating the genes that encode the formation of complement proteins leading to assembly of the MAC, which in turn further advances tissue injury. All of these factors contribute to the development of myocardial infarction subsequent to ischaemia and reperfusion. This paper provides an overview of how the complement system operates and examines the various inhibitors, both endogenous and exogenous, that regulate the complement cascade. Activation and inhibition of the complement system will be discussed primarily in the context of myocardial ischaemia and reperfusion injury.

• antibodies
• atherosclerosis
• C5a
• complement
• extracorpeal circulation
• glycosaminoglycan
• ischaemia/reperfusion
• membrane attack complex
• preconditioning
• sCR1