Role for the alternative complement pathway in ischemia/reperfusion injury

Am J Pathol. 2003 Feb;162(2):449-55. doi: 10.1016/S0002-9440(10)63839-4.

Abstract

The terminal complement components play an important role in mediating tissue injury after ischemia and reperfusion (I/R) injury in rats and mice. However, the specific complement pathways involved in I/R injury are unknown. The role of the alternative pathway in I/R injury may be particularly important, as it amplifies complement activation and deposition. In this study, the role of the alternative pathway in I/R injury was evaluated using factor D-deficient (-/-) and heterozygote (+/-) mice. Gastrointestinal ischemia (GI) was induced by clamping the mesenteric artery for 20 minutes and then reperfused for 3 hours. Sham-operated control mice (+/- versus -/-) had similar baseline intestinal lactate dehydrogenase activity (P = ns). Intestinal lactate dehydrogenase activity was greater in -/- mice compared to +/- mice after GI/R (P = 0.02) thus demonstrating protection in the -/- mice. Intestinal myeloperoxidase activity in +/- mice was significantly greater than -/- mice after GI/R (P < 0.001). Pulmonary myeloperoxidase activity after GI/R was significantly higher in +/- than -/- mice (P = 0.03). Addition of human factor D to -/- animals restored GI/R injury and was prevented by a functionally inhibitory antibody against human factor D. These data suggest that the alternative complement pathway plays an important role in local and remote tissue injury after GI/R. Inhibition of factor D may represent an effective therapeutic approach for GI/R injury.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Complement Factor D / deficiency*
  • Complement Factor D / metabolism
  • Complement Pathway, Alternative / physiology*
  • Kinetics
  • L-Lactate Dehydrogenase / analysis
  • Mice
  • Mice, Knockout
  • Peroxidase / metabolism
  • Rats
  • Reperfusion Injury / blood*
  • Reperfusion Injury / pathology*

Substances

  • L-Lactate Dehydrogenase
  • Peroxidase
  • CFD protein, human
  • Complement Factor D
  • complement factor D, mouse