Therapeutic potential of complement inhibitors in myocardial ischaemia

Under normal conditions, the complement system functions to eradicate micro bes and other membrane bound pathogens. In other situations, complement act ivation comprises a pivotal mechanism for mediating tissue demolition in in flammatory disorders, including ischaemia/reperfusion injury. Complement-me diated tissue damage has long been recognised as a significant contributor to myocardial reperfusion injury. However, clinical use of complement inhib itors to reduce the extent of irreversible tissue injury related to reperfu sion, remains in the early stages of development. Activation of the complem ent system generates anaphylatoxins, opsonins and the lyric moiety known as the membrane attack complex (MAC). In addition, fragments of the complemen t cascade proteins (e.g., C3a and C5a) secondarily initiate processes delet erious to myocytes by recruiting and stimulating inflammatory cells, such a s neutrophils and macrophages, within the area of reperfusion. Damaged tiss ue itself, is capable of upregulating the genes that encode the formation o f 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 pap er provides an overview of how the complement system operates and examines the various inhibitors both endogenous and exogenous, that regulate the com plement cascade. Activation and inhibition of the complement system will be discussed primarily in the context of myocardial ischaemia and reperfusion injury.