Rehan Virender K, Wang Ying, Patel Sanjay, Santos Jamie, Torday John S
Department of Pediatrics, Los Angeles Biomedical Research Center at Harbor UCLA, David Geffen UCLA School of Medicine, University of California at Los Angeles, Torrance, California 90502, USA.
Pediatr Pulmonol. 2006 Jun;41(6):558-69. doi: 10.1002/ppul.20407.
Molecular disruption of homeostatic alveolar epithelial-mesenchymal interactions results in transdifferentiation of alveolar interstitial lipofibroblasts to myofibroblasts. Although this process was suggested to be a central molecular event in the pathogenesis of bronchopulmonary dysplasia (BPD), so far it has been only demonstrated in vitro; whether it also occurs in vivo is unknown. Our objectives were to determine if exposure to hyperoxia results in pulmonary alveolar lipo-to-myofibroblast transdifferentiation in vivo, and whether treatment with a potent peroxisome proliferator-activated receptor gamma (PPARgamma) (the key lipogenic fibroblast nuclear transcription factor) agonist, rosiglitazone, prevents this process. Newborn Sprague Dawley rat pups were exposed to control (21% O2), hyperoxia alone (95% O2 for 24 hr), or hyperoxia with rosiglitazone (95% O2 for 24 hr + rosiglitazone, 3 mg/kg, administered intraperitoneally) conditions. Subsequently, pups were sacrificed, and lung tissue was analyzed by morphometry, and by reverse transcription-polymerase chain reaction, Western hybridization, and immunohistochemistry for the expression of key lipogenic and myogenic markers. We observed a significant decrease in the expression of lipogenic markers, and a significant increase in the expression of myogenic markers in the hyperoxia-alone group. These hyperoxia-induced morphologic, molecular, and immunohistochemical changes were almost completely prevented by rosiglitazone. This is the first evidence of in vivo lipo-to-myofibroblast transdifferentiation and its almost complete prevention by rosiglitazone, prompting us to conclude that administration of PPARgamma agonists may be a novel, effective strategy to prevent the hyperoxia-induced lung molecular injury that has been implicated in the pathogenesis of BPD.
稳态肺泡上皮-间充质相互作用的分子破坏导致肺泡间质脂肪成纤维细胞向肌成纤维细胞转分化。尽管这一过程被认为是支气管肺发育不良（BPD）发病机制中的核心分子事件，但迄今为止仅在体外得到证实；其在体内是否也会发生尚不清楚。我们的目标是确定暴露于高氧环境是否会在体内导致肺泡脂肪成纤维细胞向肌成纤维细胞转分化，以及用强效过氧化物酶体增殖物激活受体γ（PPARγ）（关键的脂肪生成成纤维细胞核转录因子）激动剂罗格列酮进行治疗是否能阻止这一过程。将新生的斯普拉格-道利大鼠幼崽暴露于对照（21%氧气）、单纯高氧（95%氧气，持续24小时）或高氧联合罗格列酮（95%氧气，持续24小时 + 罗格列酮，3毫克/千克，腹腔注射）条件下。随后，处死幼崽，通过形态计量学以及逆转录-聚合酶链反应、蛋白质免疫印迹和免疫组织化学分析肺组织中关键脂肪生成和肌生成标志物的表达。我们观察到单纯高氧组中脂肪生成标志物的表达显著降低，而肌生成标志物的表达显著增加。罗格列酮几乎完全阻止了这些高氧诱导的形态学、分子和免疫组织化学变化。这是体内脂肪成纤维细胞向肌成纤维细胞转分化及其被罗格列酮几乎完全阻止的首个证据，促使我们得出结论，给予PPARγ激动剂可能是一种预防与BPD发病机制相关的高氧诱导肺分子损伤的新型有效策略。
