Moore C, Shen X D, Fondevila C, Gao F, Coito A J
The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Transplant Proc. 2005 May;37(4):1682-3. doi: 10.1016/j.transproceed.2005.03.146.
We investigated the effects of the connecting segment-1 (CS1) peptide, which blocks fibronectin (FN)-alpha4beta1 integrin interactions, upon recipient survival and extent of tissue injury in a well-established rat liver model of ex vivo 24-hour cold ischemia followed by isotransplantation. In this model, CS1 peptides were administered through the portal vein of rat livers prior to and after cold ischemic storage. In addition, recipients of orthotopic liver transplants (OLT) received a dose of CS1 peptides 1 hour post-OLT. CS1 peptide therapy significantly inhibited the intragraft recruitment of T lymphocytes and neutrophil activation/infiltration, and repressed important mediators of inflammation, such as cyclooxygenase-2, and inducible nitric oxide synthase expression. Importantly, CS1 peptide therapy improved function/histological preservation of liver grafts and extended their 14-day survival from 50% in control to 100% in CS1-treated OLTs. Thus, CS1 peptide-mediated blockade of FN-alpha4beta1 interaction protects against severe ischemia-reperfusion injury experienced otherwise by OLTs. These novel findings document the potential of targeting FN-alpha4beta1 in vivo interaction for improving OLT outcomes.
我们在一个成熟的大鼠肝脏模型中进行了研究，该模型先进行24小时离体冷缺血，然后进行同基因移植，以探究连接段-1（CS1）肽（其可阻断纤连蛋白（FN）与α4β1整合素的相互作用）对受体存活及组织损伤程度的影响。在这个模型中，CS1肽在冷缺血保存前后通过大鼠肝脏的门静脉给药。此外，原位肝移植（OLT）受体在OLT后1小时接受一剂CS1肽。CS1肽治疗显著抑制了移植肝内T淋巴细胞的募集以及中性粒细胞的激活/浸润，并抑制了重要的炎症介质，如环氧合酶-2和诱导型一氧化氮合酶的表达。重要的是，CS1肽治疗改善了肝移植的功能/组织学保存，并将其14天存活率从对照组的50%提高到CS1治疗的OLT组的100%。因此，CS1肽介导的FN-α4β1相互作用阻断可保护OLT免受严重的缺血再灌注损伤。这些新发现证明了靶向体内FN-α4β1相互作用以改善OLT结果的潜力。
