A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice
Songqing He, … , Xiaoping Chen, Stephen Tomlinson
Songqing He, … , Xiaoping Chen, Stephen Tomlinson
Published July 20, 2009
Citation Information: J Clin Invest. 2009;119(8):2304-2316. https://doi.org/10.1172/JCI38289.
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Research Article Hepatology

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

Abstract

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.

Authors

Songqing He, Carl Atkinson, Fei Qiao, Katherine Cianflone, Xiaoping Chen, Stephen Tomlinson

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Figure 1

Complement deficiency and inhibition protects against hepatic injury and inflammation following I/R.

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Complement deficiency and inhibition protects against hepatic injury and...
Determinations were performed using liver or serum samples prepared after 30 minutes ischemia and either 6 or 24 hours reperfusion in C3–/– mice or WT mice treated with normal saline (NS) or CR2-Crry (either 0.25 or 0.08-mg dose). (A) Serum ALT levels. (B) Histological quantification of hepatic necrosis and injury, determined 6 hours after reperfusion, on a scale of 0–4. (C) Representative H&E-stained sections 6 hours after reperfusion, with the arrow-outlined area showing widespread hepatic necrosis in WT mice. Original magnification, ×100. (D) MPO content in liver samples normalized by total protein content. (E) Serum concentration of TNF-α. (F) Serum concentration of IL-6. Serum ALT levels, histological scores, liver MPO levels, and serum TNF-α and IL-6 levels were raised significantly in all groups undergoing I/R compared with sham-operated mice. #P < 0.01 versus all IRI groups; ##P < 0.01 versus other IRI groups, respectively; *P < 0.05 versus 0.25 mg CR2-Crry group; †P < 0.05, ††P < 0.01 versus 0.08 mg CR2-Crry group. Results are expressed as mean ± SD; n = 4 for all groups.