Belknap J K, Orton E C, Ensley B, Tucker A, Stenmark K R
Developmental Lung Biology Laboratory, University of Colorado Health Sciences Center, Denver, USA.
Am J Respir Cell Mol Biol. 1997 Apr;16(4):366-71. doi: 10.1165/ajrcmb.16.4.9115746.
Thickening of peripheral pulmonary arteries (PA) in the pulmonary hypertensive neonate has been well described morphologically, but less is known regarding the role of cell proliferation in either the normal or hypertensive neonatal PA. Thus we studied DNA synthetic indices in the tunica media and tunica adventitia of four different sizes/generations of PA in normoxic calves (n = 15) and calves exposed to hypobaric hypoxia (n = 15) during the first 14 days of life. DNA synthetic indices were determined by incorporation of the thymidine analogue bromodeoxyuridine (BrdU). Hemodynamic studies confirmed a steady decline in PA pressure in normal neonatal calves during the first 2 wk of life and progressive pulmonary hypertension in the hypoxic group. Lungs were perfusion-fixed and pulmonary arteries were evaluated for BrdU incorporation by immunohistochemistry. DNA synthetic indices (BrdU-labeled cells/1,000 cells) in the tunica media from normoxic calves were highest between 4 and 7 days postpartum and decreased to their lowest levels by day 14. The highest indices were observed in smaller generations of PA in the normoxic newborn. Adventitial cells exhibited the same general pattern of BrdU incorporation except that the postpartum peak occurred earlier, at 1 to 4 days. Exposure to hypoxia significantly increased (P = 0.001) DNA synthetic indices in both the tunica media and adventitia. The highest DNA synthetic indices were observed in smaller-generation vessels. These findings indicate that the fraction of cells traversing the S phase (i.e., actively replicating in the cell cycle) in the normal neonatal pulmonary vasculature during transition are initially high compared to reported rates in hilar PA from adult rats, but then decrease by 14 days after birth. Further, exposure to hypoxia during transition dramatically increases and prolongs pulmonary vascular cell proliferation. We conclude that structural remodeling in the hypertensive neonatal PA is due partly to increased cell proliferation in the tunica media and adventitia.
肺动脉高压新生儿外周肺动脉（PA）增厚的形态学特征已有详尽描述，但关于细胞增殖在正常或高血压新生儿PA中的作用，我们所知甚少。因此，我们研究了常氧小牛（n = 15）和出生后前14天暴露于低压低氧环境的小牛（n = 15）中，四种不同大小/代次PA的中膜和外膜中的DNA合成指数。通过掺入胸苷类似物溴脱氧尿苷（BrdU）来测定DNA合成指数。血流动力学研究证实，正常新生小牛在出生后前2周PA压力稳步下降，而低氧组则出现进行性肺动脉高压。肺经灌注固定后，通过免疫组织化学评估肺动脉中BrdU的掺入情况。常氧小牛中膜的DNA合成指数（BrdU标记细胞/1000个细胞）在产后4至7天最高，到第14天降至最低水平。在常氧新生儿中，较小代次的PA观察到最高指数。外膜细胞表现出相同的BrdU掺入总体模式，只是产后峰值出现得更早，在1至4天。暴露于低氧环境显著增加（P = 0.001）了中膜和外膜中的DNA合成指数。在较小代次的血管中观察到最高的DNA合成指数。这些发现表明，与成年大鼠肺门PA报道的速率相比，正常新生儿肺血管系统在过渡期穿越S期（即在细胞周期中活跃复制）的细胞比例最初较高，但在出生后14天会下降。此外，过渡期暴露于低氧环境会显著增加并延长肺血管细胞增殖。我们得出结论，高血压新生儿PA的结构重塑部分归因于中膜和外膜中细胞增殖的增加。
