Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

Lihua Wang, Krithika Lingappan, Weiwu Jiang, Xanthi I. Couroucli, Stephen E. Welty, Binoy Shivanna, Roberto Barrios, Gangduo Wang, M Khan, Frank J. Gonzalez, L. Jackson Roberts, Bhagavatula Moorthy

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight- to ten-week-old WT (C57BL/6) or Cyp1a2-/- mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24-72 h. Lung injury was assessed by determining the ratio of lung weight/body weight (LW/BW) and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2-/- mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, and IL-6 and TNF-α levels and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde- and 4-hydroxynonenal-protein adducts and pulmonary isofurans compared to WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation of hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.

Original languageEnglish (US)
Pages (from-to)147-159
Number of pages13
JournalFree Radical Biology and Medicine
Volume82
DOIs
StatePublished - 2015

Fingerprint

Cytochrome P-450 CYP1A2
Lung Injury
Cytochromes
Hyperoxia
F2-Isoprostanes
Lung
Oxidative stress
Lipid Peroxidation
Lipids
Cytochrome P-450 Enzyme System
Oxidative Stress
Body Weight
Histology
Dinoprost
Weights and Measures
Metabolites
Malondialdehyde
Infiltration
Metabolism
Neutrophil Infiltration

Keywords

  • Acute lung injury
  • ARDS
  • CYP1A2
  • Free radicals
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Wang, L., Lingappan, K., Jiang, W., Couroucli, X. I., Welty, S. E., Shivanna, B., ... Moorthy, B. (2015). Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury. Free Radical Biology and Medicine, 82, 147-159. https://doi.org/10.1016/j.freeradbiomed.2015.01.019

Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury. / Wang, Lihua; Lingappan, Krithika; Jiang, Weiwu; Couroucli, Xanthi I.; Welty, Stephen E.; Shivanna, Binoy; Barrios, Roberto; Wang, Gangduo; Khan, M; Gonzalez, Frank J.; Jackson Roberts, L.; Moorthy, Bhagavatula.

In: Free Radical Biology and Medicine, Vol. 82, 2015, p. 147-159.

Research output: Contribution to journalArticle

Wang, L, Lingappan, K, Jiang, W, Couroucli, XI, Welty, SE, Shivanna, B, Barrios, R, Wang, G, Khan, M, Gonzalez, FJ, Jackson Roberts, L & Moorthy, B 2015, 'Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury', Free Radical Biology and Medicine, vol. 82, pp. 147-159. https://doi.org/10.1016/j.freeradbiomed.2015.01.019
Wang, Lihua ; Lingappan, Krithika ; Jiang, Weiwu ; Couroucli, Xanthi I. ; Welty, Stephen E. ; Shivanna, Binoy ; Barrios, Roberto ; Wang, Gangduo ; Khan, M ; Gonzalez, Frank J. ; Jackson Roberts, L. ; Moorthy, Bhagavatula. / Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury. In: Free Radical Biology and Medicine. 2015 ; Vol. 82. pp. 147-159.
@article{8890c43b076b44bbbdb8ea3dd4bfe0e4,
title = "Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury",
abstract = "Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight- to ten-week-old WT (C57BL/6) or Cyp1a2-/- mice were exposed to hyperoxia (>95{\%} O2) or maintained in room air for 24-72 h. Lung injury was assessed by determining the ratio of lung weight/body weight (LW/BW) and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2-/- mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, and IL-6 and TNF-α levels and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde- and 4-hydroxynonenal-protein adducts and pulmonary isofurans compared to WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation of hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.",
keywords = "Acute lung injury, ARDS, CYP1A2, Free radicals, Oxidative stress",
author = "Lihua Wang and Krithika Lingappan and Weiwu Jiang and Couroucli, {Xanthi I.} and Welty, {Stephen E.} and Binoy Shivanna and Roberto Barrios and Gangduo Wang and M Khan and Gonzalez, {Frank J.} and {Jackson Roberts}, L. and Bhagavatula Moorthy",
year = "2015",
doi = "10.1016/j.freeradbiomed.2015.01.019",
language = "English (US)",
volume = "82",
pages = "147--159",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury

AU - Wang, Lihua

AU - Lingappan, Krithika

AU - Jiang, Weiwu

AU - Couroucli, Xanthi I.

AU - Welty, Stephen E.

AU - Shivanna, Binoy

AU - Barrios, Roberto

AU - Wang, Gangduo

AU - Khan, M

AU - Gonzalez, Frank J.

AU - Jackson Roberts, L.

AU - Moorthy, Bhagavatula

PY - 2015

Y1 - 2015

N2 - Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight- to ten-week-old WT (C57BL/6) or Cyp1a2-/- mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24-72 h. Lung injury was assessed by determining the ratio of lung weight/body weight (LW/BW) and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2-/- mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, and IL-6 and TNF-α levels and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde- and 4-hydroxynonenal-protein adducts and pulmonary isofurans compared to WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation of hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.

AB - Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight- to ten-week-old WT (C57BL/6) or Cyp1a2-/- mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24-72 h. Lung injury was assessed by determining the ratio of lung weight/body weight (LW/BW) and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2-/- mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, and IL-6 and TNF-α levels and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde- and 4-hydroxynonenal-protein adducts and pulmonary isofurans compared to WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation of hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo.

KW - Acute lung injury

KW - ARDS

KW - CYP1A2

KW - Free radicals

KW - Oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=84924965694&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924965694&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2015.01.019

DO - 10.1016/j.freeradbiomed.2015.01.019

M3 - Article

C2 - 25680282

AN - SCOPUS:84924965694

VL - 82

SP - 147

EP - 159

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -