Jayle C, Milinkevitch S, Favreau F, Doucet C, Richer J P, Deretz S, Mauco G, Rabb H, Hauet T
INSERM E0324, Centre Hospitalier et Universitaire and Faculte de Medecine, Poitiers, France.
Kidney Int. 2006 May;69(10):1749-55. doi: 10.1038/sj.ki.5000335.
Experiments in rodents have demonstrated an important role for selectins in kidney ischemia-reperfusion injury (IRI). However, the relevance of this in larger mammals, as well as the impact on long-term structure and function is unknown. We tested the hypothesis that small molecule selectin ligand inhibition attenuates IRI, cellular inflammation, and long-term effects on renal interstitial fibrosis. We used a porcine model of kidney IRI and used Texas Biotechnology Corporation (TBC)-1269, a selectin ligand inhibitor. Renal function, tissue inflammation, and tubulointerstitial fibrosis development were evaluated up to 16 weeks. Both warm and cold ischemia models were studied for relevance to native and transplant kidney injury. Pigs treated with TBC-1269 during 45 min of warm ischemia (WI) showed significantly increased glomerular filtration rate compared to control animals. In pigs with severe IRI (WI for 60 min), TBC-1269 treatment during IRI significantly increased renal recovery. Cellular inflammation was strongly reduced, particularly influx of CD4 cells. Quantitative measurement of fibrosis by picrosirius red staining showed strong reduction in TBC-1269-treated groups. TBC-1269 also reduced cold IRI, inflammation, and fibrosis in kidneys preserved for 24 h at 4 degrees C and autotransplanted. The selectin ligand inhibitor TBC-1269 provides a novel and effective approach to attenuate IRI in both warm and cold ischemia in large mammals, in both short and long terms. Selectin ligand inhibition is an attractive strategy for evaluation in human kidney IRI.
啮齿动物实验已证明选择素在肾脏缺血再灌注损伤（IRI）中起重要作用。然而，这在大型哺乳动物中的相关性以及对长期结构和功能的影响尚不清楚。我们检验了以下假设：小分子选择素配体抑制可减轻IRI、细胞炎症以及对肾间质纤维化的长期影响。我们使用了猪肾脏IRI模型，并使用了选择素配体抑制剂德州生物技术公司（TBC）-1269。对肾功能、组织炎症和肾小管间质纤维化发展进行了长达16周的评估。研究了热缺血和冷缺血模型与天然肾和移植肾损伤的相关性。在45分钟热缺血（WI）期间用TBC-1269治疗的猪与对照动物相比，肾小球滤过率显著增加。在严重IRI（WI 60分钟）的猪中，IRI期间TBC-1269治疗显著提高了肾脏恢复。细胞炎症明显减轻，尤其是CD4细胞的流入。通过天狼星红染色对纤维化进行定量测量显示，TBC-1269治疗组显著减轻。TBC-1269还减少了在4℃保存24小时后自体移植的肾脏中的冷IRI、炎症和纤维化。选择素配体抑制剂TBC-1269提供了一种新的有效方法，可在短期和长期内减轻大型哺乳动物热缺血和冷缺血中的IRI。选择素配体抑制是一种在人类肾脏IRI中进行评估的有吸引力的策略。
