| Summary: | Bronchopulmonary dysplasia (BPD) is a morbid lung disease distinguished by lung alveolar and vascular simplification. Hyperoxia, an important BPD causative factor, increases extracellular signal-regulated kinases (ERK)-1/2 expression, whereas decreased lung endothelial cell <i>ERK2</i> expression reduces angiogenesis and potentiates hyperoxia-mediated BPD in mice. However, ERK1′s role in experimental BPD is unclear. Thus, we hypothesized that hyperoxia-induced experimental BPD would be more severe in global <i>ERK1</i>-knockout (<i>ERK1</i><sup>-/-</sup>) mice than their wild-type (<i>ERK1</i><sup>+/+</sup> mice) littermates. We determined the extent of lung development, ERK1/2 expression, inflammation, and oxidative stress in <i>ERK1</i><sup>-/-</sup> and <i>ERK1</i><sup>+/+</sup> mice exposed to normoxia (FiO<sub>2</sub> 21%) or hyperoxia (FiO<sub>2</sub> 70%). We also quantified the extent of angiogenesis and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) production in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs) with normal and decreased <i>ERK1</i> signaling. Compared with <i>ERK1</i><sup>+/+</sup> mice, <i>ERK1</i><sup>-/-</sup> mice displayed increased pulmonary ERK2 activation upon hyperoxia exposure. However, the extent of hyperoxia-induced inflammation, oxidative stress, and interrupted lung development was similar in <i>ERK1</i><sup>-/-</sup> and <i>ERK1</i><sup>+/+</sup> mice. <i>ERK1</i> knockdown in HPMECs increased ERK2 activation at baseline, but did not affect in vitro angiogenesis and hyperoxia-induced H<sub>2</sub>O<sub>2</sub> production. Thus, we conclude <i>ERK1</i> is dispensable for hyperoxia-induced experimental BPD due to compensatory ERK2 activation.
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