The Role of the Complement System in Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion (I/R) injury is a common clinical event with the potential to seriously affect, and sometimes kill, the patient. Interruption of blood supply causes ischemia, which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissues initiates a cascade of pathology that leads to additional cell or tissue injury. I/R is a potent inducer of complement activation that results in the production of a number of inflammatory mediators. The use of specific inhibitors to block complement activation has been shown to prevent local tissue injury after I/R. Clinical and experimental studies in gut, kidney, limb, and liver have shown that I/R results in local activation of the complement system and leads to the production of the complement factors C3a, C5a, and the membrane attack complex. The novel inhibitors of complement products may find wide clinical application because there are no effective drug therapies currently available to treat I/R injuries.

Activation of the Lectin Pathway by Natural IgM in a Model of Ischemia/Reperfusion Injury

“…A large body of evidence has accumulated over the past two decades implicating a major role for the complement system in ischemia/reperfusion (I/R) 4 injury in humans (13)(14)(15)(16) and animals (12,(17)(18)(19)(20)(21)(22)(23). Studies (24 -26) using mice deficient in complement C4, C3, total Ig (Rag7 Ϫ/Ϫ ), or a subset of B-1 lymphocytes (Cr2 Ϫ/Ϫ ) found they were protected in the hind limb and intestinal I/R models.…”

The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization

“…Prolonged intestinal ischemia rapidly causes significant and irreversible tissue damage. Although restoration of blood flow to ischemic tissue is critical for tissue salvage, reperfusion also introduces inflammatory changes that exacerbate injury (3). This intestinal ischemia-reperfusion (IR) injury is associated with local and systemic inflammatory responses that ultimately progress to multiorgan failure and often to death (2).…”

“…Complement activation triggers the generation of cleavage products, including the anaphylatoxins C3a and C5a (5). C5a plays a particularly pivotal role in the modulation of the immune response during IR injuries by inducing chemotaxis and activation of granulocytes, with subsequent release of reactive oxygen species and other tissue-destructive mediators (3,6,7). In contrast to C5a, the biological actions of C3a in IR injuries have received limited attention.…”

Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis

“…10 Although having a defensive role in physiological conditions, these components have recently been implicated in the pathogenesis of many inflammatory and immunological diseases. [11][12][13][14][15][16] These activation products are not necessarily the initiating factors in the inflammatory disorders, they appear to be responsible for promoting and perpetuating inflammatory reactions. Among the complement activation products, C5a is one of the most potent inflammatory peptides, with a broad spectrum of functions.…”