Extracellular Signal-Regulated Kinase 1 Alone Is Dispensable for Hyperoxia-Mediated Alveolar and Pulmonary Vascular Simplification in Neonatal Mice

Abstract

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 ERK2 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 ERK1-knockout (ERK1-/-) mice than their wild-type (ERK1+/+ mice) littermates. We determined the extent of lung development, ERK1/2 expression, inflammation, and oxidative stress in ERK1-/- and ERK1+/+ mice exposed to normoxia (FiO2 21%) or hyperoxia (FiO2 70%). We also quantified the extent of angiogenesis and hydrogen peroxide (H2O2) production in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs) with normal and decreased ERK1 signaling. Compared with ERK1+/+ mice, ERK1-/- 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 ERK1-/- and ERK1+/+ mice. ERK1 knockdown in HPMECs increased ERK2 activation at baseline, but did not affect in vitro angiogenesis and hyperoxia-induced H2O2 production. Thus, we conclude ERK1 is dispensable for hyperoxia-induced experimental BPD due to compensatory ERK2 activation.

Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs

“…Yet, our data reveal that Areg similarly stimulates ERK1/2 in developing lung ECs. Further, we previously demonstrated that ERK1/2 activation positively influences lung EC homeostasis in developing lungs [31,34,38]. CD34 + cells maintain tissue homeostasis [71] and are activated during tissue injury, increasing the expression of growth repair tissue factors such as Areg [72].…”

“…To address the knowledge gap of the effects of Areg on the developing lung vasculature, we studied the effects of hyperoxia (HO), a commonly used insult to model BPD using newborn mice [26][27][28][29] and lung endothelial cells (ECs) [30,31], on Areg expression in whole lungs and lung ECs. We also examined if and how Areg influences the effects of HO on lung angiogenesis.…”

Hyperoxia Disrupts Lung Lymphatic Homeostasis in Neonatal Mice

“…Thus, we performed in vitro and in vivo experiments to elucidate the effects of hyperoxia (HO), a well-known insult to cause experimental and clinical BPD [ 18 , 33 , 34 , 35 ], on human and murine lymphatic endothelial homeostasis. We used our established in vitro [ 36 , 37 ] and in vivo [ 35 ] HO models to test the hypothesis that HO exposure disrupts lymphatic endothelial homeostasis.…”