Abdelwahab Abdellatif, Gopallawa Indiwari, Piasecki Christopher C, Gewolb Ira H, Uhal Bruce D
College of Human Medicine, Department of Pediatrics and Human Development, Division of Neonatology, Michigan State University, East Lansing, MI 48824.
Department of Physiology, Michigan State University, East Lansing, MI 48824.
Jacobs J Pulmonol. 2016 Sep;2(3). Epub 2016 Jun 15.
Previous work from this laboratory demonstrated that apoptosis is regulated by a local angiotensin (ANG) system in alveolar epithelial cells (AECs). Autocrine generation of angiotensin II (ANGII) in response to endogenous or xenobiotic inducers is required for apoptosis in adult rat AECs and in AEC-derived human lung carcinoma cell line A549. Therefore, we hypothesized that a similar mechanism might also be involved in bleomycin (Bleo)-induced murine neonatal lung injury.
To investigate the local production of angiotensinogen (AGT) and ANGII in neonatal lung injury, lung explants were obtained from C57/BL6 wild type neonatal mice and were treated with Bleo in the presence or absence of an angiotensin converting enzyme (ACE) inhibitor. AGT protein, ANGII levels and caspase-9 were then measured.
Exposure to Bleo significantly induced AGT protein (p<0.02), extracellular ANGII levels (p< 0.005) and the active form of caspase-9 (p<0.05) in neonatal lung tissue. Further, Bleo inducetion of both AGT protein and of caspase-9 were prevented by the ACE inhibitor lisinopril.
These data clearly demonstrate the synthesis of AGT and ANGII in the lungs of neonates in response to Bleo. Furthermore, they suggest that manipulation of the angiotensin system may hold therapeutic potential for neonatal lung injury.
本实验室先前的研究表明，细胞凋亡受肺泡上皮细胞（AECs）局部血管紧张素（ANG）系统的调控。成年大鼠AECs和AEC来源的人肺癌细胞系A549发生细胞凋亡时，需要自分泌生成血管紧张素II（ANGII）以响应内源性或外源性诱导剂。因此，我们推测类似的机制可能也参与博来霉素（Bleo）诱导的小鼠新生儿肺损伤。
为研究新生儿肺损伤中血管紧张素原（AGT）和ANGII的局部产生情况，从C57/BL6野生型新生小鼠获取肺组织外植体，在有或无血管紧张素转换酶（ACE）抑制剂的情况下用Bleo处理。然后检测AGT蛋白、ANGII水平和半胱天冬酶-9。
暴露于Bleo显著诱导新生小鼠肺组织中的AGT蛋白（p<0.02）、细胞外ANGII水平（p<0.005）和半胱天冬酶-9的活性形式（p<0.05）。此外，ACE抑制剂赖诺普利可阻止Bleo诱导AGT蛋白和半胱天冬酶-9。
这些数据清楚地证明了新生小鼠肺中AGT和ANGII的合成是对Bleo的反应。此外，它们表明对血管紧张素系统的调控可能对新生儿肺损伤具有治疗潜力。
