Takada M, Nadeau K C, Shaw G D, Tilney N L
Harvard Medical School, and Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Transplantation. 1997 Dec 15;64(11):1520-5. doi: 10.1097/00007890-199712150-00003.
Increasing clinical evidence suggests that delayed initial function secondary to ischemia/reperfusion injury alone, and particularly in combination with early episodes of acute rejection, reduces kidney allograft survival over time.
We investigated changes developing over the long term following a standardized ischemia/reperfusion insult in a Lewis rat model. The left kidney was isolated in a uninephrectomized host and cooled, and the pedicle was clamped for 45 min. Animals were followed for 48 weeks after initial renal injury. Organs were removed serially (4, 8, 16, 24, 32, 40, and 48 weeks) for immunohistology and reverse transcriptase polymerase chain reaction.
Progressive proteinuria developed after 8 weeks. By immunohistology, CD4+ leukocytes and ED-1+ macrophages infiltrated the ischemic organs in parallel with up-regulation of major histocompatibility complex class II antigen expression. Because macrophages have been shown to be critical in chronic changes in other models, they were examined primarily in these studies. By reverse transcriptase polymerase chain reaction, macrophage-derived, fibrosis-inducing factors (transforming growth factor-beta, interleukin 6, and tumor necrosis factor-alpha) remained highly and constantly expressed throughout the follow-up period. The long-term influence of initial treatment with the soluble form of P-selectin glycoprotein ligand-1, a soluble ligand for P- and E-selectin, was then examined. All functional and structural changes remained at relative baseline, similar to uninephrectomized controls.
These data suggest that blocking the initial selectin-mediated step after ischemia/reperfusion injury, which triggers significant early cellular and molecular events, also reduces later renal dysfunction and tissue damage over time. In part, the findings may be explained by the sparing of functioning nephron units, which if destroyed or compromised by the original insult, may contribute to long-term graft failure. This approach may be important clinically in the transplantation of kidneys from non-heart-beating or marginal donors or organs experiencing prolonged ischemic times.
越来越多的临床证据表明，单纯由缺血/再灌注损伤继发的延迟初始功能，尤其是与早期急性排斥反应同时发生时，会随着时间的推移降低肾移植存活率。
我们在Lewis大鼠模型中研究了标准化缺血/再灌注损伤后长期发生的变化。在单侧肾切除的宿主中分离左肾并进行冷却，肾蒂夹闭45分钟。在初始肾损伤后对动物进行48周的随访。在不同时间点（4、8、16、24、32、40和48周）依次取出器官进行免疫组织学和逆转录聚合酶链反应检测。
8周后出现进行性蛋白尿。通过免疫组织学检查，CD4 +白细胞和ED-1 +巨噬细胞浸润缺血器官，同时主要组织相容性复合体II类抗原表达上调。由于巨噬细胞在其他模型的慢性变化中已被证明至关重要，因此在这些研究中主要对其进行了检测。通过逆转录聚合酶链反应，巨噬细胞衍生的纤维化诱导因子（转化生长因子-β、白细胞介素6和肿瘤坏死因子-α）在整个随访期间一直保持高表达。然后研究了用P-选择素糖蛋白配体-1的可溶性形式（P-和E-选择素的可溶性配体）进行初始治疗的长期影响。所有功能和结构变化均保持在相对基线水平，类似于单侧肾切除的对照组。
这些数据表明，阻断缺血/再灌注损伤后最初的选择素介导步骤，该步骤会引发显著的早期细胞和分子事件，也能随着时间的推移减少后期的肾功能障碍和组织损伤。部分研究结果可能是由于保留了功能正常的肾单位，如果这些肾单位被原始损伤破坏或损害，可能会导致长期移植失败。这种方法在临床上对于来自非心跳或边缘供体的肾脏移植或经历长时间缺血的器官移植可能很重要。
