Complement depletion protects lupus-prone mice from ischemia-reperfusion-initiated organ injury

Abstract

Ischemia-reperfusion (IR) injury causes a vigorous immune response that is amplified by complement activation, leading to local and remote tissue damage. Using MRL/lpr mice, which are known to experience accelerated tissue damage after mesenteric IR injury, we sought to evaluate whether complement inhibition mitigates organ damage. We found that complement depletion with cobra venom factor protected mice from local and remote lung tissue damage. Protection from injury was associated with less complement (C3) and membrane attack complex deposition, less neutrophil infiltration, and lower levels of local proinflammatory cytokine production. In addition, complement depletion was able to decrease the level of oxidative stress as measured by glutathione peroxidase 1 mRNA levels and superoxide dismutase activity. Furthermore, blockage of C5a receptor protected MRL/lpr mice from local tissue damage, but not from remote lung tissue damage. In conclusion, although treatments with cobra venom factor and C5a receptor antagonist were able to protect mice from local tissue damage, treatment with C5a receptor antagonist was not able to protect mice from remote lung tissue damage, implying that more factors contribute to the development of remote tissue damage after IR injury. These data also suggest that complement inhibition at earlier, rather than late, stages can have clinical benefit in conditions that are complicated with IR injury.

Activation of C3a receptor is required in cigarette smoke-mediated emphysema

“…C3 and its activated downstream products play a role in activation of the acquired immune system during the development of several autoimmune inflammatory diseases. For instance, lupus-prone mice depleted of C3 are protected from the development of organ injury; also complement C3 inhibitor, acting upon sites of complement activation effectively ameliorates collagen-induced arthritis 40 , 41 . Further, activation of C3 is required for effective trafficking of myeloid dendritic cells from the lung to the thoracic draining lymph node during influenza virus infection 42 .…”

Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia

“…Complement depletion by CVF has been shown to reduce tissue damage in mice subjected to IR (16)(17)(18)(19). To address whether circulating complement is responsible for the intestinal injury during ischemia, CVF was administered to mice 24 and 16 h prior to mesenteric ischemia, IR, or sham procedures.…”

last Overpressure Induced Pulmonary and Intestinal Damage is Ameliorated by Post-injury Decay Accelerating Factor Injection

“…BOP pulmonary and intestinal tissue injury shows general similarity to Ischemia/Reperfusion (I/R) injury in its subsequent increased inflammation and delayed injury response. Complement inhibition therapy have been demonstrated to decrease severity of I/R injuries to these tissues [13,14]. Decay Accelerating Factor (DAF) is a naturally present complement-inhibitory protein in humans that binds cells and prevents assembly of both C4b2a and C3bBb, the classical and alternative pathway C3 convertases.…”