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Am J Transl Res 2013;5(6):594-607
Original Article
Effects of a superoxide dismutase mimetic on biomarkers of lung
angiogenesis and alveolarization during hyperoxia with intermittent
hypoxia
Michael Chang, Fayez Bany-Mohammed, M Cristina Kenney, Kay D Beharry
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California Irvine, Irvine, CA;
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Miller Children’s Hospital, Long Beach, CA;
Departments of Ophthalmology and Pathology, University of California Irvine, Irvine, CA; Departments of Pediatrics
and Ophthalmology, SUNY Downstate Medical Center, Brooklyn, NY
Received July 16, 2013; Accepted August 25, 2013; Epub September 25, 2013; Published September 30, 2013
Abstract: Extremely premature neonates requiring oxygen therapy develop an accumulation of reactive oxygen
species (ROS), impaired alveolarization and dysmorphic pulmonary vasculature. Regulators of ROS (i.e.
antioxidants), alveolarization (i.e. matrix metalloproteinases - MMPs) and microvascular maturation (i.e. vascular
endothelial growth factor - VEGF) are altered in bronchopulmonary dysplasia (BPD). We tested the hypothesis
that early treatment with MnTBAP, a superoxide dismutase mimetic and superoxide anion and peroxynitrite
scavenger, alters lung biomarkers of angiogenesis and alveolarization during hyperoxia with intermittent hypoxia
(IH) in neonatal rats. Neonatal rats were exposed to 50% O2 with brief IH episodes (12% O2) from P0 to P14, or
to room air (RA). On P0, P1 & P2, the pups received a daily IP injection of 1, 5, or 10 mg/kg MnTBAP, or saline. At
P14, the pups were either euthanized, or allowed to recover in RA until P21. RA littermates were similarly treated.
Lung VEGF, sVEGFR-1, MMP-2, MMP-9 and TIMP-1 were determined. Low-dose MnTBAP (1 mg/kg) prevented the
increase in lung VEGF induced by intermittent hypoxia noted in the control group. This dose was also effective for
decreasing MMP-9 and MMP-9/TIMP-1 ratio suggesting an anti-inflammatory effect for MnTBAP. IH decreased
MMP-2 with no ameliorating effect by MnTBAP. Our data demonstrate that brief, repeated intermittent hypoxia
during hyperoxia can alter biomarkers responsible for normal microvascular and alveolar development. In
addition to prevention of hypoxic events, the use of antioxidants needs to be explored as a possible therapeutic
intervention in neonates at risk for the development of oxidative lung injury. (AJTR1307002).
Keywords: Antioxidants, hyperoxia, intermittent hypoxia, matrix metalloproteinases, tissue inhibitor of
metalloproteinase
Address correspondence to: Kay D Beharry, Departments of Pediatrics/Div. Neonatology & Ophthalmology,
Director, Neonatal-Perinatal Medicine Clinical & Translational Research Labs, Dept. Pediatrics/Div. Neonatal-
Perinatal Medicine, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 49,
Brooklyn, NY, 11203, USA. Tel: 718-270-1475; Fax: 718-270-1985; E-mail: kbeharry@downstate.edu
Original Article
Effects of a superoxide dismutase mimetic on biomarkers of lung
angiogenesis and alveolarization during hyperoxia with intermittent
hypoxia
Michael Chang, Fayez Bany-Mohammed, M Cristina Kenney, Kay D Beharry
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California Irvine, Irvine, CA;
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Miller Children’s Hospital, Long Beach, CA;
Departments of Ophthalmology and Pathology, University of California Irvine, Irvine, CA; Departments of Pediatrics
and Ophthalmology, SUNY Downstate Medical Center, Brooklyn, NY
Received July 16, 2013; Accepted August 25, 2013; Epub September 25, 2013; Published September 30, 2013
Abstract: Extremely premature neonates requiring oxygen therapy develop an accumulation of reactive oxygen
species (ROS), impaired alveolarization and dysmorphic pulmonary vasculature. Regulators of ROS (i.e.
antioxidants), alveolarization (i.e. matrix metalloproteinases - MMPs) and microvascular maturation (i.e. vascular
endothelial growth factor - VEGF) are altered in bronchopulmonary dysplasia (BPD). We tested the hypothesis
that early treatment with MnTBAP, a superoxide dismutase mimetic and superoxide anion and peroxynitrite
scavenger, alters lung biomarkers of angiogenesis and alveolarization during hyperoxia with intermittent hypoxia
(IH) in neonatal rats. Neonatal rats were exposed to 50% O2 with brief IH episodes (12% O2) from P0 to P14, or
to room air (RA). On P0, P1 & P2, the pups received a daily IP injection of 1, 5, or 10 mg/kg MnTBAP, or saline. At
P14, the pups were either euthanized, or allowed to recover in RA until P21. RA littermates were similarly treated.
Lung VEGF, sVEGFR-1, MMP-2, MMP-9 and TIMP-1 were determined. Low-dose MnTBAP (1 mg/kg) prevented the
increase in lung VEGF induced by intermittent hypoxia noted in the control group. This dose was also effective for
decreasing MMP-9 and MMP-9/TIMP-1 ratio suggesting an anti-inflammatory effect for MnTBAP. IH decreased
MMP-2 with no ameliorating effect by MnTBAP. Our data demonstrate that brief, repeated intermittent hypoxia
during hyperoxia can alter biomarkers responsible for normal microvascular and alveolar development. In
addition to prevention of hypoxic events, the use of antioxidants needs to be explored as a possible therapeutic
intervention in neonates at risk for the development of oxidative lung injury. (AJTR1307002).
Keywords: Antioxidants, hyperoxia, intermittent hypoxia, matrix metalloproteinases, tissue inhibitor of
metalloproteinase
Address correspondence to: Kay D Beharry, Departments of Pediatrics/Div. Neonatology & Ophthalmology,
Director, Neonatal-Perinatal Medicine Clinical & Translational Research Labs, Dept. Pediatrics/Div. Neonatal-
Perinatal Medicine, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 49,
Brooklyn, NY, 11203, USA. Tel: 718-270-1475; Fax: 718-270-1985; E-mail: kbeharry@downstate.edu
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