Abstract
Premature infants often develop serious clinical complications associated with respiratory failure and hyperoxic lung injury that includes lung inflammation and alterations in lung development. The goal of these studies is to test the hypothesis that there are differences in the course of lung injury in newborn mice exposed to 85% or >95% oxygen that provide models to address the differential effects of oxidation and inflammation. Our results indicate differences between the 85% and >95% O2 exposure groups by day 14 in weight gain and lung alveolarization. Inflammation, assessed by neutrophil counts, was observed in both hyperoxia groups by day 3 but was dramatically greater in the >95% O2-exposed groups by day 14 and associated with greater developmental deficits. Cytoplasmic phospholipase A2, cyclooxygenase-2, and 5-lipoxygenase levels were elevated but no patterns of differences were observed between exposure groups. Prostaglandins D2, E2, and F2α were increased in the tissues from mouse pups exposed to >95% O2 at 7 d indicating a differential expression of cyclooxygenase-2 products. Our data indicate that there are differences in the models of 85% or >95% O2 exposure and these differences may provide mechanistic insights into hyperoxic lung injury in an immature system.
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Abbreviations
- BPD:
-
bronchopulmonary dysplasia
- COX-2:
-
cyclooxygenase-2
- cPLA2:
-
cytoplasmic phospholipase A2
- LO:
-
lipoxygenase
- LT:
-
leukotriene
- PG:
-
prostaglandin
- RA:
-
room air;,
- TBX:
-
thromboxane
References
Wispe JR, Roberts RJ 1987 Molecular basis of pulmonary oxygen toxicity. Clin Perinatol 14: 651–666
O'Donovan DJ, Rogers LK, Kelley DK, Welty SE, Ramsay PL, Smith CV 2002 CoASH and CoASSG levels in lungs of hyperoxic rats as potential biomarkers of intramitochondrial oxidant stresses. Pediatr Res 51: 346–353
Tipple TE, Welty SE, Rogers LK, Hansen TN, Choi YE, Kehrer JP, Smith CV 2007 Thioredoxin-related mechanisms in hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 37: 405–413
Wong YL, Smith CV, McMicken HW, Rogers LK, Welty SE 2001 Mitochondrial thiol status in the liver is altered by exposure to hyperoxia. Toxicol Lett 123: 179–193
Zhao B, Ramsay PL, Park MS, Welty SE, De MA 2000 In vivo and in vitro analysis of hyperoxia-induced gene expression in mouse lung and mouse transformed Clara cells. Ann NY Acad Sci 923: 346–347
Crapo JD, Barry BE, Foscue H, Shelburne J 1980 Structural and biochemical changes in rat lungs ocurring during exposures to lethal and adaptive doses of oxygen. Am Rev Respir Dis 122: 123–143
Warner BB, Stuart LA, Papes RA, Wispe JR 1998 Functional and pathological effects of prolonged hyperoxia in neonatal mice. Am J Physiol 275: L110–L117
Park MS, Rieger-Fackeldey E, Schanbacher BL, Cook AC, Bauer JA, Rogers LK, Hansen TN, Welty SE, Smith CV 2007 Altered expressions of fibroblast growth factor receptors and alveolarization in neonatal mice exposed to 85% oxygen. Pediatr Res 62: 652–657
Rehan VK, Wang Y, Patel S, Santos J, Torday JS 2006 Rosiglitazone, a peroxisome proliferator-activated receptor-g agonist, prevents hyperoxiz-induced neonatoal rat lung injury in vivo. Pediatr Pulmonol 41: 558–569
Nakamura T, Henson PM, Murphy RC 1998 Occurrence of oxidized metabolites of arachidonic acid esterified to phospholipids in murine lung tissue. Anal Biochem 262: 23–32
Pappas CT, Obara H, Bensch KG, Northway WH Jr 1983 Effect of prolonged exposure to 80% oxygen on the lung of the newborn mouse. Lab Invest 48: 735–748
McGrath-Morrow SA, Stahl J 2001 Apoptosis in neonatal murine lung exposed to hyperoxia. Am J Respir Cell Mol Biol 25: 150–155
Ogihara T, Hirano K, Morinobu T, Kim HS, Hiroi M, Ogihara H, Tamai H 1999 Raised concentrations of aldehyde lipid peroxidation products in premature infants with chronic lung disease. Arch Dis Child Fetal Neonatal Ed 80: F21–F25
Nycyk JA, Drury JA, Cooke RW 1998 Breath pentane as a marker for lipid peroxidation and adverse outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed 79: F67–F69
Speer CP 2003 Inflammation and bronchopulmonary dysplasia. Semin Neonatol 8: 29–38
Massaro D, Massaro GD 2002 Invited review: pulmonary alveoli: formation, the “call for oxygen,” and other regulators. Am J Physiol Lung Cell Mol Physiol 282: L345–L358
Massaro GD, Olivier J, Dzikowski C, Massaro D 1990 Postnatal development of lung alveoli: suppression by 13% O2 and a critical period. Am J Physiol 258: L321–L327
Alejandre-Alcazar MA, Kwapiszewska G, Reiss I, Amarie OV, Marsh LM, Sevilla-Perez J, Wygrecka M, Eul B, Kobrich S, Hesse M, Schermuly RT, Seeger W, Eickelberg O, Morty RE 2007 Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 292: L537–L549
Dieperink HI, Blackwell TS, Prince LS 2006 Hyperoxia and apoptosis in developing mouse lung mesenchyme. Pediatr Res 59: 185–190
Ramsay PL, Smith CV, Geske RS, Montgomery CA, Welty SE 1998 Dexamethasone enhancement of hyperoxic lung inflammation in rats independent of adhesion molecule expression. Biochem Pharmacol 56: 259–268
Crapo JD 1986 Morphologic changes in pulmonary oxygen toxicity. Annu Rev Physiol 48: 721–731
Yoshikawa S, Miyahara T, Reynolds SD, Stripp BR, Anghelescu M, Eyal FG, Parker JC 2005 Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice. J Appl Physiol 98: 1264–1271
Nagase T, Uozumi N, Aoki-Nagase T, Terawaki K, Ishii S, Tomita T, Yamamoto H, Hashizume K, Ouchi Y, Shimizu T 2003 A potent inhibitor of cytosolic phospholipase A2, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol 284: L720–L726
Simmons DL, Botting RM, Hla T 2004 Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56: 387–437
Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD 2005 Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol 174: 5033–5039
Hodges RJ, Jenkins RG, Wheeler-Jones CP, Copeman DM, Bottoms SE, Bellingan GJ, Nanthakumar CB, Laurent GJ, Hart SL, Foster ML, McAnulty RJ 2004 Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production. Am J Pathol 165: 1663–1676
Park GY, Christman JW 2006 Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases. Am J Physiol Lung Cell Mol Physiol 290: L797–L805
Manji JS, O'Kelly CJ, Leung WI, Olson DM 2001 Timing of hyperoxic exposure during alveolarization influences damage mediated by leukotrienes. Am J Physiol Lung Cell Mol Physiol 281: L799–L806
Acknowledgements
We thank Xiaomei Meng, Molly Augustine, and Kathryn Heyob for their technical support.
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This work was supported by NHLBI, HL068948.
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Rogers, L., Tipple, T., Nelin, L. et al. Differential Responses in the Lungs of Newborn Mouse Pups Exposed to 85% or >95% Oxygen. Pediatr Res 65, 33–38 (2009). https://doi.org/10.1203/PDR.0b013e31818a1d0a
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DOI: https://doi.org/10.1203/PDR.0b013e31818a1d0a


