| First Author | Ito R | Year | 2022 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 323 |
| Issue | 2 | Pages | L129-L141 |
| PubMed ID | 35762602 | Mgi Jnum | J:329957 |
| Mgi Id | MGI:7355170 | Doi | 10.1152/ajplung.00110.2022 |
| Citation | Ito R, et al. (2022) SM22alpha cell-specific HIF stabilization mitigates hyperoxia-induced neonatal lung injury. Am J Physiol Lung Cell Mol Physiol 323(2):L129-L141 |
| abstractText | 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 SM22alpha-expressing cells can limit hyperoxia-induced neonatal lung injury. We generated SM22alpha-specific HIF-1alpha-stabilized mice (SM22alpha-PHD1/2(-/-) mice) by cross-breeding SM22alpha-promotor-driven Cre recombinase mice with prolyl hydroxylase PHD1(flox/flox) and PHD2(flox/flox) mice. Neonatal mice were randomized to 21% O2 (normoxia) or 80% O2 (hyperoxia) exposure for 14 days. For the hyperoxia recovery studies, neonatal mice were recovered from normoxia for an additional 10 wk. SM22alpha-specific HIF-1alpha stabilization mitigated hyperoxia-induced lung injury and preserved microvessel density compared with control mice for both neonates and adults. In SM22alpha-PHD1/2(-/-) 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 SM22alpha-PHD1/2(-/-) compared with control mice in both normoxia and hyperoxia. Pulmonary endothelial cells (PECs) cocultured with PASMC isolated from SM22alpha-PHD1/2(-/-) mice formed more tubes and branches with greater tube length compared with PEC cocultured with PASMC isolated from SM22alpha-PHD1/2(+/+) mice. Addition of Ang2 recombinant protein further augmented tube formation for both PHD1/2(+/+) and PHD1/2(-/-) PASMC. Cell-specific deletion of PHD1 and 2 selectively increases HIF-1alpha expression in SM22alpha-expressing cells and protects neonatal lung development despite prolonged hyperoxia exposure. HIF stabilization in SM22alpha-expressing cells preserved endothelial cell proliferation, microvascular density, increased angiopoietin-2 expression, and lung structure, suggesting a role for cell-specific HIF-1alpha stabilization to prevent neonatal lung injury. |
