Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California.
Am J Physiol Lung Cell Mol Physiol. 2022 Aug 1;323(2):L129-L141. doi: 10.1152/ajplung.00110.2022. Epub 2022 Jun 28.
Though survival rates for preterm infants are improving, the incidence of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Histologically, BPD is characterized by larger and fewer alveoli. Hypoxia-inducible factors (HIFs) may be protective in the context of hyperoxia-induced lung injury, but the cell-specific effects of HIF expression in neonatal lung injury remain unknown. Thus, we sought to determine whether HIF stabilization in SM22α-expressing cells can limit hyperoxia-induced neonatal lung injury. We generated SM22α-specific HIF-1α-stabilized mice ( mice) by cross-breeding SM22α-promotor-driven Cre recombinase mice with prolyl hydroxylase and mice. Neonatal mice were randomized to 21% O (normoxia) or 80% O (hyperoxia) exposure for 14 days. For the hyperoxia recovery studies, neonatal mice were recovered from normoxia for an additional 10 wk. SM22α-specific HIF-1α stabilization mitigated hyperoxia-induced lung injury and preserved microvessel density compared with control mice for both neonates and adults. In mice, pulmonary artery endothelial cells (PAECs) were more proliferative and pulmonary arteries expressed more collagen IV compared with control mice, even under hyperoxic conditions. Angiopoietin-2 (Ang2) mRNA expression in pulmonary artery smooth muscle cells (PASMC) was greater in compared with control mice in both normoxia and hyperoxia. Pulmonary endothelial cells (PECs) cocultured with PASMC isolated from mice formed more tubes and branches with greater tube length compared with PEC cocultured with PASMC isolated from mice. Addition of Ang2 recombinant protein further augmented tube formation for both and PASMC. Cell-specific deletion of PHD1 and 2 selectively increases HIF-1α expression in SM22α-expressing cells and protects neonatal lung development despite prolonged hyperoxia exposure. HIF stabilization in SM22α-expressing cells preserved endothelial cell proliferation, microvascular density, increased angiopoietin-2 expression, and lung structure, suggesting a role for cell-specific HIF-1α stabilization to prevent neonatal lung injury.
尽管早产儿的存活率在提高，但婴儿期慢性肺部疾病（支气管肺发育不良，BPD）的发病率仍然很高。从组织学上看，BPD 的特征是肺泡更大且更少。缺氧诱导因子（HIFs）在高氧诱导的肺损伤中可能具有保护作用，但 HIF 在新生儿肺损伤中的细胞特异性表达的作用尚不清楚。因此，我们试图确定在 SM22α 表达细胞中稳定 HIF 是否可以限制高氧诱导的新生儿肺损伤。我们通过将 SM22α 启动子驱动的 Cre 重组酶小鼠与脯氨酰羟化酶和小鼠杂交，生成了 SM22α 特异性 HIF-1α 稳定的小鼠（小鼠）。新生小鼠被随机分为 21% O（常氧）或 80% O（高氧）暴露 14 天。对于高氧恢复研究，新生小鼠从常氧中恢复 10 周。与对照小鼠相比，SM22α 特异性 HIF-1α 稳定化减轻了高氧诱导的肺损伤并维持了微血管密度，无论是在新生儿还是成年小鼠中都是如此。在 小鼠中，与对照小鼠相比，肺动脉内皮细胞（PAECs）在高氧条件下增殖更多，肺动脉表达更多的胶原蛋白 IV。与对照小鼠相比，高氧和常氧条件下，肺动脉平滑肌细胞（PASMC）中的血管生成素-2（Ang2）mRNA 表达更高。与来自 小鼠的 PASMC 共培养的肺内皮细胞（PECs）形成的管和分支更多，管长度更长，而与来自 小鼠的 PASMC 共培养的 PEC 则更少。添加 Ang2 重组蛋白进一步增加了两种 和 PASMC 的管形成。PHD1 和 2 的细胞特异性缺失选择性地增加了 SM22α 表达细胞中的 HIF-1α 表达，并在延长高氧暴露的情况下保护新生儿肺发育。SM22α 表达细胞中 HIF 的稳定化维持了内皮细胞的增殖、微血管密度、增加了血管生成素-2 的表达，并维持了肺结构，这表明细胞特异性 HIF-1α 稳定化在预防新生儿肺损伤方面具有重要作用。
