Intracellular activation of complement 3 mediates intestinal tissue damage during mesenteric ischemia (INC1P.356)

Ischemia of the intestine followed by reperfusion leads to significant local and remote organ injury (IRI) attributed to inflammatory elements acting during the reperfusion phase. Whether ischemia contributes to IRI has not been addressed. Careful evaluation of intestinal tissue following ischemia we noticed significant local injury, which was associated by increased production of complement 3 (C3) by intestinal epithelial cells. C3-deficient mice failed to exhibit similar injury and while cobra venom factor pre-treatment, which depleted all complement in the circulation, eliminated all IRI, but it failed to mitigate injury during the ischemia phase. C3 was activated within the epithelial cells during ischemia as indicated by immunocytochemistry and Caco2 (colon epithelial cancer cells) produced C3a after LPS stimulation. Production of C3a was decreased in the presence of cathepsin inhibitors. In conclusion, intestinal epithelial cells when subjected to ischemia can produce and activate C3 and initiate intestinal damage, which is amplified during the reperfusion phase.