Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities
Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities
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DOI：
10.1182/blood-2010-09-306357
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发表时间：
2011-03-31
期刊：
影响因子：
20.3
通讯作者：
Erzurum, Serpil C.
中科院分区：
文献类型：
--
作者：
Farha, Samar;Asosingh, Kewal;Erzurum, Serpil C.
肺动脉高压(PAH)是一种以高循环CD34(+)CD133(+)前体细胞和内皮细胞病理性表达缺氧诱导因子-1α(HIF-1α)为特征的增殖性血管病变。CD34(+)CD133(+)祖细胞在PAH患者的骨髓、血液和肺动脉中的数量均高于健康对照组。HIF诱导的髓系激活因子促红细胞生成素、干细胞因子(SCF)和肝细胞生长因子(HGF)在PAH血中的水平也高于正常水平，并与疾病严重程度有关。人PAH肺原代内皮细胞产生的HGF和祖细胞募集因子基质衍生因子1α(SDF-1α)高于对照组肺内皮细胞，因此可能有助于骨髓的激活。尽管PAH患者的循环血元素数量正常，但髓系和红系的造血细胞改变以及网状纤维证实了一种亚临床骨髓增殖过程。出乎意料的是，对家族性PAH患者未受影响的家庭成员的骨髓祖细胞和网织蛋白的评估发现了类似的髓系异常。总之，这些结果表明PAH与髓系异常有关，其中一些可能与病变的肺血管系统增加HIF诱导因子的产生有关，但在未受影响的家系中的发现表明，髓系异常可能是疾病过程中固有的。(血。2011；117(13)：3485-3493)
Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34(+)CD133(+) proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha). Here, CD34(+)CD133(+) progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 alpha (SDF-1 alpha) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. (Blood. 2011;117(13):3485-3493)