Frid Maria G, Brunetti Jacqueline A, Burke Danielle L, Carpenter Todd C, Davie Neil J, Reeves John T, Roedersheimer Mark T, van Rooijen Nico, Stenmark Kurt R
Department of Pediatrics, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262, USA.
Am J Pathol. 2006 Feb;168(2):659-69. doi: 10.2353/ajpath.2006.050599.
Vascular remodeling in chronic hypoxic pulmonary hypertension includes marked fibroproliferative changes in the pulmonary artery (PA) adventitia. Although resident PA fibroblasts have long been considered the primary contributors to these processes, we tested the hypothesis that hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage, termed fibrocytes. Using two neonatal animal models (rats and calves) of chronic hypoxic pulmonary hypertension, we demonstrated a dramatic perivascular accumulation of mononuclear cells of a monocyte/macrophage lineage (expressing CD45, CD11b, CD14, CD68, ED1, ED2). Many of these cells produced type I collagen, expressed alpha-smooth muscle actin, and proliferated, thus exhibiting mesenchymal cell characteristics attributed to fibrocytes. The blood-borne origin of these cells was confirmed in experiments wherein circulating monocytes/macrophages of chronically hypoxic rats were in vivo-labeled with DiI fluorochrome via liposome delivery and subsequently identified in the remodeled pulmonary, but not systemic, arterial adventitia. The DiI-labeled cells that appeared in the vessel wall expressed monocyte/macrophage markers and procollagen. Selective depletion of this monocytic cell population, using either clodronate-liposomes or gadolinium chloride, prevented pulmonary adventitial remodeling (ie, production of collagen, fibronectin, and tenascin-C and accumulation of myofibroblasts). We conclude that circulating mesenchymal precursors of a monocyte/macrophage lineage, including fibrocytes, are essential contributors to hypoxia-induced pulmonary vascular remodeling.
慢性缺氧性肺动脉高压中的血管重塑包括肺动脉外膜显著的纤维增生性改变。尽管肺动脉成纤维细胞长期以来一直被认为是这些过程的主要促成因素，但我们检验了这样一个假说，即缺氧诱导的肺血管重塑需要募集循环中的单核细胞/巨噬细胞谱系的间充质前体细胞，即纤维细胞。使用两种慢性缺氧性肺动脉高压的新生动物模型（大鼠和小牛），我们证明了单核细胞/巨噬细胞谱系的单核细胞在血管周围大量积聚（表达CD45、CD11b、CD14、CD68、ED1、ED2）。这些细胞中的许多产生I型胶原，表达α-平滑肌肌动蛋白，并进行增殖，因此表现出纤维细胞所具有的间充质细胞特征。在实验中证实了这些细胞的血源性，在这些实验中，通过脂质体递送用DiI荧光染料对慢性缺氧大鼠的循环单核细胞/巨噬细胞进行体内标记，随后在重塑的肺动脉而非体循环动脉外膜中鉴定出这些细胞。出现在血管壁中的DiI标记细胞表达单核细胞/巨噬细胞标志物和前胶原。使用氯膦酸脂质体或氯化钆选择性清除这个单核细胞群体，可防止肺外膜重塑（即胶原、纤连蛋白和肌腱蛋白-C的产生以及肌成纤维细胞的积聚）。我们得出结论，循环中的单核细胞/巨噬细胞谱系的间充质前体细胞，包括纤维细胞，是缺氧诱导的肺血管重塑的重要促成因素。
