Perinatal changes in superoxide generation in the ovine lung: Alterations associated with increased pulmonary blood flow

Shruti Sharma, Sanjiv Kumar, Dean A. Wiseman, Suphin Kallarackal, Sumant Ponnala, Manal Elgaish, Jing Tian, Jeffrey R. Fineman, Stephen Matthew Black

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Although alterations in ROS generating systems are well described in several vascular disorders, there is very limited information on the perinatal regulation of these systems in the lung both during normal development and in pulmonary hypertension. Thus, this study was undertaken to explore how the two predominant superoxide generating systems, nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and xanthine oxidase (XO), are developmentally regulated in control lambs and in our established lamb model of increased pulmonary blood flow (Shunt) over the first 2 months of life. We found that the levels of p47phox, p67phox, and Rac1 subunits of NADPH oxidase complex were altered. During the first two months of life there was no change in p47phox protein levels in either normal or Shunt lambs. However, both p67phox and Rac1 protein levels decreased over time. In addition, p47phox protein levels were significantly increased in shunt lambs at 2- and 4-, but not 8-weeks of age compared to age-matched controls while levels of the p67phox subunit were decreased at 8-weeks of age in the Shunts but unchanged at other time periods. Furthermore, Rac1 protein expression was significantly increased in the Shunts only at 4 weeks of age. These data correlated with a significant increase in NADPH oxidase dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. During normal development XO levels significantly increased over time in normal lambs but significantly decreased in the Shunts. In addition, XO protein levels were significantly increased in the Shunt at 2- and 4-weeks of age but significantly decreased at 8-weeks. Again this correlated with a significant increase in XO dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. Collectively, our findings suggest that NADPH oxidase and XO are major contributors to superoxide generation both during the normal development and during the development of pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)38-52
Number of pages15
JournalVascular Pharmacology
Volume53
Issue number1-2
DOIs
StatePublished - Jul 1 2010

Fingerprint

Xanthine Oxidase
Superoxides
Sheep
NADP
Oxidoreductases
rac1 GTP-Binding Protein
Lung
Pulmonary Hypertension
Proteins
Blood Vessels
neutrophil cytosol factor 67K

Keywords

  • Allopurinol
  • Apocynin
  • NADPH oxidase
  • Pulmonary hypertension
  • Xanthine oxidase

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Cite this

Perinatal changes in superoxide generation in the ovine lung : Alterations associated with increased pulmonary blood flow. / Sharma, Shruti; Kumar, Sanjiv; Wiseman, Dean A.; Kallarackal, Suphin; Ponnala, Sumant; Elgaish, Manal; Tian, Jing; Fineman, Jeffrey R.; Black, Stephen Matthew.

In: Vascular Pharmacology, Vol. 53, No. 1-2, 01.07.2010, p. 38-52.

Research output: Contribution to journalArticle

Sharma, Shruti ; Kumar, Sanjiv ; Wiseman, Dean A. ; Kallarackal, Suphin ; Ponnala, Sumant ; Elgaish, Manal ; Tian, Jing ; Fineman, Jeffrey R. ; Black, Stephen Matthew. / Perinatal changes in superoxide generation in the ovine lung : Alterations associated with increased pulmonary blood flow. In: Vascular Pharmacology. 2010 ; Vol. 53, No. 1-2. pp. 38-52.
@article{5f5b2f14c11a487c94f11209816688c8,
title = "Perinatal changes in superoxide generation in the ovine lung: Alterations associated with increased pulmonary blood flow",
abstract = "Although alterations in ROS generating systems are well described in several vascular disorders, there is very limited information on the perinatal regulation of these systems in the lung both during normal development and in pulmonary hypertension. Thus, this study was undertaken to explore how the two predominant superoxide generating systems, nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and xanthine oxidase (XO), are developmentally regulated in control lambs and in our established lamb model of increased pulmonary blood flow (Shunt) over the first 2 months of life. We found that the levels of p47phox, p67phox, and Rac1 subunits of NADPH oxidase complex were altered. During the first two months of life there was no change in p47phox protein levels in either normal or Shunt lambs. However, both p67phox and Rac1 protein levels decreased over time. In addition, p47phox protein levels were significantly increased in shunt lambs at 2- and 4-, but not 8-weeks of age compared to age-matched controls while levels of the p67phox subunit were decreased at 8-weeks of age in the Shunts but unchanged at other time periods. Furthermore, Rac1 protein expression was significantly increased in the Shunts only at 4 weeks of age. These data correlated with a significant increase in NADPH oxidase dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. During normal development XO levels significantly increased over time in normal lambs but significantly decreased in the Shunts. In addition, XO protein levels were significantly increased in the Shunt at 2- and 4-weeks of age but significantly decreased at 8-weeks. Again this correlated with a significant increase in XO dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. Collectively, our findings suggest that NADPH oxidase and XO are major contributors to superoxide generation both during the normal development and during the development of pulmonary hypertension.",
keywords = "Allopurinol, Apocynin, NADPH oxidase, Pulmonary hypertension, Xanthine oxidase",
author = "Shruti Sharma and Sanjiv Kumar and Wiseman, {Dean A.} and Suphin Kallarackal and Sumant Ponnala and Manal Elgaish and Jing Tian and Fineman, {Jeffrey R.} and Black, {Stephen Matthew}",
year = "2010",
month = "7",
day = "1",
doi = "10.1016/j.vph.2010.03.005",
language = "English (US)",
volume = "53",
pages = "38--52",
journal = "Vascular Pharmacology",
issn = "1537-1891",
publisher = "Elsevier Inc.",
number = "1-2",

}

TY - JOUR

T1 - Perinatal changes in superoxide generation in the ovine lung

T2 - Alterations associated with increased pulmonary blood flow

AU - Sharma, Shruti

AU - Kumar, Sanjiv

AU - Wiseman, Dean A.

AU - Kallarackal, Suphin

AU - Ponnala, Sumant

AU - Elgaish, Manal

AU - Tian, Jing

AU - Fineman, Jeffrey R.

AU - Black, Stephen Matthew

PY - 2010/7/1

Y1 - 2010/7/1

N2 - Although alterations in ROS generating systems are well described in several vascular disorders, there is very limited information on the perinatal regulation of these systems in the lung both during normal development and in pulmonary hypertension. Thus, this study was undertaken to explore how the two predominant superoxide generating systems, nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and xanthine oxidase (XO), are developmentally regulated in control lambs and in our established lamb model of increased pulmonary blood flow (Shunt) over the first 2 months of life. We found that the levels of p47phox, p67phox, and Rac1 subunits of NADPH oxidase complex were altered. During the first two months of life there was no change in p47phox protein levels in either normal or Shunt lambs. However, both p67phox and Rac1 protein levels decreased over time. In addition, p47phox protein levels were significantly increased in shunt lambs at 2- and 4-, but not 8-weeks of age compared to age-matched controls while levels of the p67phox subunit were decreased at 8-weeks of age in the Shunts but unchanged at other time periods. Furthermore, Rac1 protein expression was significantly increased in the Shunts only at 4 weeks of age. These data correlated with a significant increase in NADPH oxidase dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. During normal development XO levels significantly increased over time in normal lambs but significantly decreased in the Shunts. In addition, XO protein levels were significantly increased in the Shunt at 2- and 4-weeks of age but significantly decreased at 8-weeks. Again this correlated with a significant increase in XO dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. Collectively, our findings suggest that NADPH oxidase and XO are major contributors to superoxide generation both during the normal development and during the development of pulmonary hypertension.

AB - Although alterations in ROS generating systems are well described in several vascular disorders, there is very limited information on the perinatal regulation of these systems in the lung both during normal development and in pulmonary hypertension. Thus, this study was undertaken to explore how the two predominant superoxide generating systems, nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and xanthine oxidase (XO), are developmentally regulated in control lambs and in our established lamb model of increased pulmonary blood flow (Shunt) over the first 2 months of life. We found that the levels of p47phox, p67phox, and Rac1 subunits of NADPH oxidase complex were altered. During the first two months of life there was no change in p47phox protein levels in either normal or Shunt lambs. However, both p67phox and Rac1 protein levels decreased over time. In addition, p47phox protein levels were significantly increased in shunt lambs at 2- and 4-, but not 8-weeks of age compared to age-matched controls while levels of the p67phox subunit were decreased at 8-weeks of age in the Shunts but unchanged at other time periods. Furthermore, Rac1 protein expression was significantly increased in the Shunts only at 4 weeks of age. These data correlated with a significant increase in NADPH oxidase dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. During normal development XO levels significantly increased over time in normal lambs but significantly decreased in the Shunts. In addition, XO protein levels were significantly increased in the Shunt at 2- and 4-weeks of age but significantly decreased at 8-weeks. Again this correlated with a significant increase in XO dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. Collectively, our findings suggest that NADPH oxidase and XO are major contributors to superoxide generation both during the normal development and during the development of pulmonary hypertension.

KW - Allopurinol

KW - Apocynin

KW - NADPH oxidase

KW - Pulmonary hypertension

KW - Xanthine oxidase

UR - http://www.scopus.com/inward/record.url?scp=77952428833&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952428833&partnerID=8YFLogxK

U2 - 10.1016/j.vph.2010.03.005

DO - 10.1016/j.vph.2010.03.005

M3 - Article

C2 - 20362073

AN - SCOPUS:77952428833

VL - 53

SP - 38

EP - 52

JO - Vascular Pharmacology

JF - Vascular Pharmacology

SN - 1537-1891

IS - 1-2

ER -