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DEVELOPMENTAL SUSCEPTIBILITY TO HYPEROXIC LUNG INJURY

DEVELOPMENTAL SUSCEPTIBILITY TO HYPEROXIC LUNG INJURY. Sara Berkelhamer , MD Northwestern University Lurie Children’s Hospital. Background: Oxidative Lung Injury. Reactive oxygen species (ROS) are generated with exposure to supraphysiologic oxygen

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DEVELOPMENTAL SUSCEPTIBILITY TO HYPEROXIC LUNG INJURY

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  1. DEVELOPMENTAL SUSCEPTIBILITY TO HYPEROXIC LUNG INJURY Sara Berkelhamer, MD Northwestern University Lurie Children’s Hospital

  2. Background: Oxidative Lung Injury • Reactive oxygen species (ROS) are generated with exposure to supraphysiologic oxygen • ROS cause damage to proteins, lipids and DNA • Animal models demonstrate that high FiO2 causes lung injury and arrested lung development • Lung injury is greatest in the most premature infants • Even brief exposure to 90% O2 during resuscitation increased the risk of BPD in 24-28w infants (Vento, 2009)

  3. mitochondria BAX O2 O2 plasma membrane NOX SOD1 catalase O2- H2O2 OH− JNK O2 ETC BAX SOD2 catalase O2- H2O2 OH- Modified from Li, et al, Current Respiratory Medicine Reviews, 2005. death factors

  4. 1. Hypothesis: developmental differences exist in ROS generation and cellular response to supraphysiologic oxygen

  5. Methods • In vitro studies • Intact lung slices and isolated alveolar cells • Live cell imaging using a redox sensor, RoGFP • Whole lung isolation for protein and mRNA analysis • In vivo exposures to 75% O2 (Biospherix Chamber) • Lung analysis • Protein and mRNA • Morphometry • Heart analysis • RVH by Fulton’s Index (RV/LV+S)

  6. Immature Lung Models Murine Intact Lung Slices Rat Primary AT2 Cells

  7. RoGFP: Sensor of redox state Reduced Oxidized Reduced Oxidized

  8. HyperoxiaInduces Exaggerated Mitochondrial Oxidative Stress in AEC of Immature Lung Slices RoGFP: Alveolar Cells Free Radical Biology, in revision

  9. HyperoxiaInduces Exaggerated Mitochondrial Oxidative Stress Response in Immature AT2 Free Radical Biology, in revision

  10. HyperoxiaInduces Comparable Oxidative StressResponse in Immature and Adult PASMCof Lung Slices A RoGFP: PA Smooth Muscle Cells Free Radical Biology, in revision

  11. Antioxidant Expression Matures Postnatally Free Radical Biology, in revision

  12. 24h of HyperoxiaInduces Increased SOD Activity in Adult but Not Immature Lung SOD MnSOD Free Radical Biology, in revision

  13. 24h HyperoxiaInduces Increased NOX1 mRNA and Protein Expression in Immature but Not Adult Lung mRNA protein Free Radical Biology, in revision

  14. EUK134 Attenuates Hyperoxia-Induced Increase in NOX1 Expression in Immature Lung Free Radical Biology, in revision

  15. Hyperoxia Induces Increased Cell Death in Immature but not Adult Lung Slices Free Radical Biology, in revision

  16. Summary • Mitochondrial ROS are generated within minutes of exposure to supraphysiologic oxygen • Immature alveolar lung cells demonstrate exaggerated mitochondrial oxidative stress in hyperoxia • ROS generation may be further amplified in the immature lung via up-regulation of NOX1 • Immature lung slices demonstrate increased susceptibility to hyperoxia-induced cell death

  17. 2. Hypothesis: A critical developmental window may exist in which exposure to supraphysiologic oxygen results in compromised lung development

  18. Model: In vivo exposure Control P0-3 P4-7 BPD Day 0 1 2 3 4 5 6 7 14 = 21% O2 = 75% O2

  19. 72h of Hyperoxia at P0-3 but not P4-7 Induces Persistent RVH * * Control P0-3 P4-7

  20. 72h of Hyperoxia at P0-3 but not P4-7 Disrupts Alveolarization * *

  21. Model: Developmental Susceptibility

  22. Clinical Implications • Supraphysiologic oxygen should be used with great caution in premature infants • A critical window may exist during which there is increased susceptibility to oxidative injury • Antioxidants targeted to the mitochondria or delivered directly to alveoli may represent novel therapeutic approaches

  23. Acknowledgements Paul Schumacker, PhD Molly Ball AnkurDatta DanijelaDokic Gina Kim Paul Mungai SimranSabharwal Jacqueline Schreiwer Gregory Waypa Kathryn Farrow, MD, PhD Lyubov Czech Robin Steinhorn, MD Stephen Wedgwood Neonatal Resuscitation Program Young Investigator’s Award, 2011

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