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 3

Reconstitution of C3–/– mice with ASP following PHx enhances either regeneration or injury depending on dose, and C5L2 (putative ASP receptor) deficiency increases injury and impairs regeneration.

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Reconstitution of C3–/– mice with ASP following PHx enhances either rege...
A 15-μg or 50-μg dose of ASP was administered to C3–/– mice and a 15-μg dose of ASP was administered to C5L2–/– mice immediately after surgery, and all determinations were made at 48 hours after PHx. (A) Serum ALT levels. (B) Histological scores. (C) Assessment of regeneration by BrdU incorporation. (D) Restitution of liver weight. (E) Forty-eight-hour survival. (F) Western blot assay for phosphorylated form of STAT3 at 3 hours after PHx. Reconstitution of C3–/– mice with low-dose ASP but not high-dose ASP significantly increased 2-day survival. Note that phospho-STAT3 (p-STAT3) levels are strongly reduced in both C5L2–/– and C3–/– mice compared with WT mice. A 15-μg dose of ASP restored activation of STAT3 in C3–/– mice but not C5L2–/– mice. #P < 0.05, ##P < 0.01 versus the C3–/– normal saline group; *P < 0.05, **P < 0.01 versus the WT group, respectively. For survival study, n = 10 for each group; all other studies, n = 4–6. Results are expressed as mean ± SD.