TY - JOUR
T1 - Extracellular Signal-Regulated Kinase 1 Alone Is Dispensable for Hyperoxia-Mediated Alveolar and Pulmonary Vascular Simplification in Neonatal Mice
AU - Menon, Renuka T.
AU - Thapa, Shyam
AU - Shrestha, Amrit Kumar
AU - Barrios, Roberto
AU - Shivanna, Binoy
N1 - Funding Information:
Funding: This work was supported by the National Institutes of Science Grant (R01HL139594 and R03HD103823 to B.S. and P30DK056338 to the Digestive Disease Center Core at Baylor College of Medicine) and funding from Texas Children’s Hospital Pediatric Pilot Award and Baseball for Babies to B.S.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/6/8
Y1 - 2022/6/8
N2 - Bronchopulmonary dysplasia (BPD) is a morbid lung disease distinguished by lung alveo-lar 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.
AB - Bronchopulmonary dysplasia (BPD) is a morbid lung disease distinguished by lung alveo-lar 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.
KW - bronchopulmonary dysplasia
KW - extracellular signal-regulated kinases 1 and 2
KW - hydrogen peroxide
KW - hyperoxia
KW - neonatal HPMECs
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U2 - 10.3390/antiox11061130
DO - 10.3390/antiox11061130
M3 - Article
C2 - 35740027
AN - SCOPUS:85131417922
SN - 2076-3921
VL - 11
JO - Antioxidants
JF - Antioxidants
IS - 6
M1 - 1130
ER -