MESENCHYMAL CELLS ISOLATED AFTER ACUTE LUNG INJURY MANIFEST AN ENHANCED PROLIFERATIVE PHENOTYPE
MESENCHYMAL CELLS ISOLATED AFTER ACUTE LUNG INJURY MANIFEST AN ENHANCED PROLIFERATIVE PHENOTYPE
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DOI：
10.1172/jci116052
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发表时间：
1992-11-01
影响因子：
15.9
通讯作者：
BITTERMAN, P
中科院分区：
文献类型：
--
作者：
CHEN, B;POLUNOVSKY, V;BITTERMAN, P
急性肺损伤后，间充质细胞迁移到肺泡空气空间，在那里它们增殖并存款结缔组织大分子。在疾病过程的早期，炎性细胞衍生的营养因子调节这些间充质细胞功能。然而，在那些死亡的患者中，即使炎症反应减弱，纤维增生反应仍在继续，导致广泛的肺泡内纤维化。因此，我们假设从急性肺泡纤维化死亡的个体中获得的肺间充质细胞将表现出独立于持续外源性信号的增强的增殖能力。为了检验这一假设，在限定培养基中分析了从死于急性肺损伤的患者（n = 3）制备的间充质细胞的体外生长特性，并与从死于组织学正常肺的患者（n = 3）类似制备的间充质细胞的体外生长特性进行了比较。分离物的特点是间充质细胞通过使用形态学和免疫组化标准。与这一假设雅阁的是，从肺损伤患者中分离的间充质细胞在完全缺乏外源性肽生长因子的情况下在3天内翻倍，达到约15 × 10（3）个细胞/cm 2的饱和密度。正如预期的那样，来自正常个体的肺间充质细胞的数量未能显著增加。与这种增殖表型一致，立即早期细胞分裂周期基因c-fos和c-jun在从损伤肺制备的每个细胞株中组成型表达，但在来自对照肺的细胞株中不表达。观察到的增殖表型在细胞的第五次传代培养中保持稳定。尽管有这些增殖特性，但三个独立的标准表明来自受损肺的间充质细胞没有转化：正常核型;体外有限寿命（9-10次传代）;以及不能在患有严重联合免疫缺陷的小鼠中传播。这些数据支持了急性肺损伤后间充质细胞表现出增强的增殖状态的假设。
After acute lung injury, mesenchymal cells migrate into the alveolar airspace where they proliferate and deposit connective tissue macromolecules. Early in the disease process, inflammatory cell-derived trophic factors modulate these mesenchymal cell functions. However, in those patients who die, even as the inflammatory response abates, the fibroproliferative response continues, resulting in extensive intraalveolar fibrosis. We therefore hypothesized that lung mesenchymal cells obtained from individuals dying with acute alveolar fibrosis would manifest an enhanced proliferative capacity that was independent of persistent exogenous signals. To examine this hypothesis, the in vitro growth properties of mesenchymal cells prepared from patients dying with acute lung injury (n = 3) were analyzed in defined medium and compared with those of mesenchymal cells similarly prepared from patients dying with histologically normal lungs (n = 3). Isolates were characterized as mesenchymal cells by using morphological and immunohistochemical criteria. In accord with the hypothesis, mesenchymal cells isolated from lung-injured patients doubled within 3 d in the complete absence of exogenous peptide growth factors, reaching a saturation density of approximately 15 x 10(3) cells/cm2. As expected, lung mesenchymal cells from normal individuals failed to significantly increase in number. Consistent with this proliferative phenotype, the immediate early cell division cycle genes c-fos and c-jun were constitutively expressed in each cell strain prepared from injured lungs, but not in those from control lungs. The observed proliferative phenotype was stable through the fifth subcultivation of the cells. Despite these proliferative properties, three separate criteria indicated the mesenchymal cells from injured lungs were not transformed: normal karyotype; finite lifespan in vitro (9-10 subcultivations); and inability to disseminate in mice with severe combined immunodeficiency. These data support the hypothesis that mesenchymal cells manifest an enhanced proliferative state after acute lung injury.