A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

J Clin Invest. 2009 Aug;119(8):2304-16. doi: 10.1172/JCI38289. Epub 2009 Jul 20.


Massive liver resection and small-for-size liver transplantation pose a therapeutic challenge, due to increased susceptibility of the remnant/graft to ischemia reperfusion injury (IRI) and impaired regeneration. We investigated the dual role of complement in IRI versus regeneration in mice. Complement component 3 (C3) deficiency and complement inhibition with complement receptor 2-complement receptor 1-related protein y (CR2-Crry, an inhibitor of C3 activation) provided protection from hepatic IRI, and while C3 deficiency also impaired liver regeneration following partial hepatectomy (PHx), the effect of CR2-Crry in this context was dose dependent. In a combined model of IRI and PHx, either C3 deficiency or high-dose CR2-Crry resulted in steatosis, severe hepatic injury, and high mortality, whereas low-dose CR2-Crry was protective and actually increased hepatic proliferative responses relative to control mice. Reconstitution experiments revealed an important role for the C3a degradation product acylation-stimulating protein (ASP) in the balance between inflammation/injury versus regeneration. Furthermore, liver regeneration was dependent on the putative ASP receptor, C5L2. Several potential mechanisms of hepatoprotection and recovery were identified in mice treated with low-dose CR2-Crry, including enhanced IL-6 expression and STAT3 activation, reduced hepatic ATP depletion, and attenuated oxidative stress. These data indicate that a threshold of complement activation, involving ASP and C5L2, promotes liver regeneration and suggest a balance between complement-dependent injury and regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Complement C3 / physiology*
  • Hepatectomy
  • Humans
  • Interleukin-6 / physiology
  • Liver / blood supply*
  • Liver Regeneration*
  • Mice
  • Recombinant Fusion Proteins / pharmacology
  • Reperfusion Injury / etiology*
  • STAT3 Transcription Factor / physiology
  • Tumor Necrosis Factor-alpha / physiology


  • CR2-Crry fusion protein, mouse
  • Complement C3
  • Interleukin-6
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Alanine Transaminase