Fondevila C, Shen X-D, Duarte S, Busuttil R W, Coito A J
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Am J Transplant. 2009 Oct;9(10):2240-50. doi: 10.1111/j.1600-6143.2009.02759.x. Epub 2009 Jul 22.
The serious need for expanding the donor population has attracted attention to the use of steatotic donor livers in orthotopic liver transplantation (OLT). However, steatotic livers are highly susceptible to hepatic ischemia-reperfusion injury (IRI). Expression of fibronectin (FN) by endothelial cells is an important feature of hepatic response to injury. We report the effect of a cyclic RGD peptide with high affinity for the alpha5beta1, the FN integrin receptor, in a rat model of steatotic liver cold ischemia, followed by transplantation. RGD peptide therapy ameliorated steatotic IRI and improved the recipient survival rate. It significantly inhibited the recruitment of monocyte/macrophages and neutrophils, and depressed the expression of pro-inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and interferon (IFN)-gamma. Moreover, it resulted in profound inhibition of metalloproteinase-9 (MMP-9) expression, a gelatinase implied in leukocyte migration in damaged livers. Finally, we show that RGD peptide therapy reduced the expression of the 17-kDa active caspase-3 and the number of apoptotic cells in steatotic OLTs. The observed protection against steatotic liver IRI by the cyclic RGD peptides with high affinity for the alpha5beta1 integrin suggests that this integrin is a potential therapeutic target to allow the successful utilization of marginal steatotic livers in transplantation.
扩大供体群体的迫切需求已引发人们对在原位肝移植（OLT）中使用脂肪变性供肝的关注。然而，脂肪变性肝脏对肝缺血再灌注损伤（IRI）高度敏感。内皮细胞表达纤连蛋白（FN）是肝脏对损伤反应的一个重要特征。我们报告了一种对α5β1（FN整合素受体）具有高亲和力的环状RGD肽在脂肪变性肝脏冷缺血大鼠模型中的作用，随后进行移植。RGD肽疗法改善了脂肪变性IRI并提高了受体存活率。它显著抑制单核细胞/巨噬细胞和中性粒细胞的募集，并抑制促炎介质如诱导型一氧化氮合酶（iNOS）和干扰素（IFN）-γ的表达。此外，它还导致金属蛋白酶-9（MMP-9）表达的显著抑制，MMP-9是一种参与受损肝脏中白细胞迁移的明胶酶。最后，我们表明RGD肽疗法降低了脂肪变性OLT中17-kDa活性半胱天冬酶-3的表达和凋亡细胞的数量。对α5β1整合素具有高亲和力的环状RGD肽对脂肪变性肝脏IRI的保护作用表明，这种整合素是一个潜在的治疗靶点，有助于在移植中成功利用边缘性脂肪变性肝脏。
