A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice
A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice
复制标题
DOI：
10.1172/jci38289
复制
发表时间：
2009-08-01
影响因子：
15.9
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
--
作者：
He, Songqing;Atkinson, Carl;Tomlinson, Stephen
由于残肝/移植物对缺血再灌注损伤（IRI）和再生受损的易感性增加，大面积肝切除和小体积肝移植提出了治疗挑战。我们研究了补体在小鼠IRI与再生中的双重作用。补体成分3（C3）缺乏和补体受体2-补体受体1相关蛋白y（CR2-Crry，一种C3激活抑制剂）的补体抑制提供了对肝IRI的保护，而C3缺乏也损害了部分肝切除术（PHx）后的肝再生，CR2-Crry在这种情况下的作用是剂量依赖性的。在IRI和P14 x的联合模型中，C3缺乏或高剂量CR2-Crry导致脂肪变性、严重肝损伤和高死亡率，而低剂量CR2-Crry具有保护作用，实际上相对于对照小鼠增加了肝脏增殖反应。重构实验揭示了C3 a降解产物酰化刺激蛋白（ASP）在炎症/损伤与再生之间的平衡中的重要作用。此外，肝脏再生依赖于推定的ASP受体C5 L2。在用低剂量CR2-Crry处理的小鼠中确定了几种潜在的肝保护和恢复机制，包括增强的IL-6表达和STAT 3活化、减少的肝脏ATP消耗和减弱的氧化应激。这些数据表明，涉及ASP和C5 L2的补体激活阈值促进肝再生，并表明补体依赖性损伤和再生之间的平衡。
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 P14x, 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.