Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Jul;301(1):L125-34. doi: 10.1152/ajplung.00074.2011. Epub 2011 Apr 29.
Hypoxia enhances transforming growth factor-β (TGF-β) signaling, inhibiting alveolar development and causing abnormal pulmonary arterial remodeling in the newborn lung. We hypothesized that, during chronic hypoxia, reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling may contribute to, or be caused by, excessive TGF-β signaling. To determine whether PPAR-γ was reduced during hypoxia, C57BL/6 mice were exposed to hypoxia from birth to 2 wk and evaluated for PPAR-γ mRNA and protein. To determine whether rosiglitazone (RGZ, a PPAR-γ agonist) supplementation attenuated the effects of hypoxia, mice were exposed to air or hypoxia from birth to 2 wk in combination with either RGZ or vehicle, and measurements of lung histology, function, parameters related to TGF-β signaling, and collagen content were made. To determine whether excessive TGF-β signaling reduced PPAR-γ, mice were exposed to air or hypoxia from birth to 2 wk in combination with either TGF-β-neutralizing antibody or vehicle, and PPAR-γ signaling was evaluated. We observed that hypoxia reduced PPAR-γ mRNA and protein, in association with impaired alveolarization, increased TGF-β signaling, reduced lung compliance, and increased collagen. RGZ increased PPAR-γ signaling, with improved lung development and compliance in association with reduced collagen and TGF-β signaling. However, no reduction was noted in hypoxia-induced pulmonary vascular remodeling. Inhibition of hypoxia-enhanced TGF-β signaling increased PPAR-γ signaling. These results suggest that hypoxia-induced inhibition of lung development is associated with a mutually antagonistic relationship between reduced PPAR-γ and increased TGF-β signaling. PPAR-γ agonists may be of potential therapeutic significance in attenuating TGF-β signaling and improving alveolar development.
低氧增强转化生长因子-β（TGF-β）信号，抑制肺泡发育，并导致新生儿肺中异常的肺动脉重塑。我们假设，在慢性低氧期间，过氧化物酶体增殖物激活受体-γ（PPAR-γ）信号的减少可能导致或由 TGF-β信号的过度增加引起。为了确定低氧期间是否降低了 PPAR-γ，将 C57BL/6 小鼠从出生到 2 周暴露于低氧环境，并评估 PPAR-γ mRNA 和蛋白。为了确定罗格列酮（RGZ，PPAR-γ 激动剂）补充是否减轻了低氧的影响，将小鼠从出生到 2 周暴露于空气或低氧环境中，同时给予 RGZ 或载体，并进行肺组织学、功能、与 TGF-β信号相关的参数和胶原含量的测量。为了确定过度的 TGF-β信号是否降低了 PPAR-γ，将小鼠从出生到 2 周暴露于空气或低氧环境中，同时给予 TGF-β中和抗体或载体，并评估 PPAR-γ 信号。我们观察到，低氧降低了 PPAR-γ mRNA 和蛋白，与肺泡化受损、TGF-β 信号增加、肺顺应性降低和胶原增加有关。RGZ 增加了 PPAR-γ 信号，与胶原和 TGF-β信号减少相关的肺发育和顺应性改善有关。然而，在低氧诱导的肺血管重塑中没有观察到减少。抑制低氧增强的 TGF-β 信号增加了 PPAR-γ 信号。这些结果表明，低氧诱导的肺发育抑制与减少的 PPAR-γ 和增加的 TGF-β 信号之间存在相互拮抗的关系。PPAR-γ 激动剂在减轻 TGF-β 信号和改善肺泡发育方面可能具有潜在的治疗意义。
