Tan Xun, Juan Fan-Guo, Shah Ali Q
Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.
J Zhejiang Univ Sci B. 2017;18(1):59-69. doi: 10.1631/jzus.B1600500.
Plexiform lesions (PLs), which are often accompanied by perivascular infiltrates of mononuclear cells, represent the hallmark lesions of pulmonary arteries in humans suffering from severe pulmonary arterial hypertension (PAH). Endothelial progenitor cells (EPCs) have been recently implicated in the formation of PLs in human patients. PLs rarely develop in rodent animal models of PAH but can develop spontaneously in broiler chickens. The aim of the present study was to confirm the presence of EPCs in the PLs in broilers. The immune mechanisms involved in EPC dysfunction were also evaluated. Lungs were collected from commercial broilers at 1 to 4 weeks of age. The right/total ventricle ratios indicated normal pulmonary arterial pressures for all sampled birds. Immunohistochemistry was performed to determine the expressions of EPC markers (CD133 and VEGFR-2) and proangiogenic molecule hepatocyte growth factor (HGF) in the lung samples. An EPC/lymphocyte co-culture system was used to investigate the functional changes of EPCs under the challenge of immune cells. PLs with different cellular composition were detected in the lungs of broilers regardless of age, and they were commonly surrounded by moderate to dense perivascular mononuclear cell infiltrates. Immunohistochemical analyses revealed the presence of CD133 and VEGFR-2 cells in PLs. These structures also exhibited a strong expression of HGF. Lymphocyte co-culture enhanced EPC apoptosis and completely blocked HGF-stimulated EPC survival and in vitro tube formation. Taken together, this work provides evidence for the involvement of EPCs in the development of PLs in broilers. It is suggested that the local immune cell infiltrate might serve as a contributor to EPC dysfunction by inducing EPC death and limiting their response to angiogenic stimuli. Broiler chickens may be valuable for investigating reversibility of plexogenic arteriopathy using gene-modified inflammation-resistant EPCs.
丛状病变（PLs）常伴有单核细胞的血管周围浸润，是重度肺动脉高压（PAH）患者肺动脉的标志性病变。内皮祖细胞（EPCs）最近被认为与人类患者PLs的形成有关。PLs在PAH的啮齿动物模型中很少发生，但可在肉鸡中自发形成。本研究的目的是证实肉鸡PLs中存在EPCs。还评估了EPC功能障碍所涉及的免疫机制。收集1至4周龄商品肉鸡的肺。右心室/总心室比值表明所有采样鸡的肺动脉压正常。进行免疫组织化学以确定肺样本中EPC标志物（CD133和VEGFR-2）和促血管生成分子肝细胞生长因子（HGF）的表达。使用EPC/淋巴细胞共培养系统研究免疫细胞刺激下EPCs的功能变化。无论年龄大小，在肉鸡肺中均检测到具有不同细胞组成的PLs，它们通常被中度至密集的血管周围单核细胞浸润所包围。免疫组织化学分析显示PLs中存在CD133和VEGFR-2细胞。这些结构还强烈表达HGF。淋巴细胞共培养增强了EPC凋亡，并完全阻断了HGF刺激的EPC存活和体外管形成。综上所述，这项工作为EPCs参与肉鸡PLs的发展提供了证据。提示局部免疫细胞浸润可能通过诱导EPC死亡并限制其对血管生成刺激的反应而导致EPC功能障碍。肉鸡对于使用基因修饰的抗炎症EPCs研究丛状动脉病的可逆性可能具有重要价值。
