Solovey Anna, Kollander Rahn, Shet Arun, Milbauer Liming C, Choong Stephana, Panoskaltsis-Mortari Angela, Blazar Bruce R, Kelm Robert J, Hebbel Robert P
Vascular Biology Center and Divisions of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
Blood. 2004 Aug 1;104(3):840-6. doi: 10.1182/blood-2003-10-3719. Epub 2004 Apr 8.
Abnormal tissue factor (TF) expression has been demonstrated on blood monocytes and circulating endothelial cells in humans with sickle cell anemia. We have now studied sickle transgenic mice to help define the biology of endothelial TF expression in sickle disease. Using immunostaining of tissue sections, we find that this is confined almost exclusively to the pulmonary veins. About 15% and 13% of these exhibit TF-positive endothelium in the wild-type normal mouse and the normal human hemoglobin (HbA)-expressing control transgenic mouse, respectively. The mild sickle mouse is indistinguishable from normal (approximately 14% positive), but TF expression is significantly elevated in the moderate and severe mouse models of sickle disease (approximately 29% and approximately 41% positive, respectively). Exposure of the mild sickle mouse to hypoxia for 3 hours, followed by reoxygenation, converted its TF expression phenotype to that of the severe sickle mouse (approximately 36% positive). Pretreatment with lovastatin eliminated excessive expression of TF in the posthypoxic mild sickle mouse (approximately 16% positive) and in the more severe mouse at ambient air (approximately 21% positive). In addition to identifying tissue expression of endothelial TF in the sickle lung, these studies implicate reperfusion injury physiology in its expression and suggest a rationale for use of statins in sickle disease.
在镰状细胞贫血患者中，已证实在血液单核细胞和循环内皮细胞上存在异常的组织因子（TF）表达。我们现在研究镰状转基因小鼠，以帮助确定镰状疾病中内皮TF表达的生物学特性。通过对组织切片进行免疫染色，我们发现这几乎完全局限于肺静脉。在野生型正常小鼠和表达正常人类血红蛋白（HbA）的对照转基因小鼠中，分别约有15%和13%的肺静脉内皮细胞呈TF阳性。轻度镰状小鼠与正常小鼠无差异（约14%阳性），但在镰状疾病的中度和重度小鼠模型中，TF表达显著升高（分别约为29%和41%阳性）。轻度镰状小鼠暴露于低氧环境3小时后再给氧，其TF表达表型转变为重度镰状小鼠的表型（约36%阳性）。用洛伐他汀预处理可消除低氧后轻度镰状小鼠（约16%阳性）和更严重小鼠在常氧环境下（约21%阳性）TF的过度表达。除了确定镰状肺中内皮TF的组织表达外，这些研究还表明再灌注损伤生理学与其表达有关，并为镰状疾病中使用他汀类药物提供了理论依据。
