Abstract
Background:
Heterozygous ATP-binding-cassette subfamily A member 3 (ABCA3) mutations are associated with neonatal respiratory complications. In an adult murine model, we investigated whether Abca3 haploinsufficiency is a predisposing factor for lung injury induced by hyperoxia or mechanical ventilation.
Methods:
Abca3 haploinsufficient (Abca3+/−) and wild-type (WT) mice were prospectively randomized to 25 min of ventilation or 72 h of hyperoxia or left unchallenged in air.
Results:
As compared with WT mice, unchallenged Abca3+/− mice had significantly decreased lung phosphatidylcholine (PC) and phosphatidylglycerol (PG) levels (P < 0.02) and decreased lung compliance (P < 0.05). When ventilated for 25 min, Abca3+/− mice demonstrated a significantly greater increase in bronchoalveolar lavage (BAL) interleukins (P ≤ 0.01) and lung wet to dry ratio (P < 0.005). Hyperoxia resulted in increased compliance (P < 0.05) and total lung capacity (TLC) (P = 0.01) only in the Abca3+/− mice, consistent with enlarged alveolar spaces. The ratio of PC to PG in BAL—relevant for surfactant dysfunction—was significantly elevated by oxygen exposure, with the greatest increase in Abca3+/− mice.
Conclusion:
In a murine model, Abca3 haploinsufficiency results in an altered biochemical and lung mechanical phenotype, as well as a greater lung injury induced by hyperoxia or mechanical ventilation. The inability to maintain a normal PC/PG ratio appears to play a key role.
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References
Yamano G, Funahashi H, Kawanami O, et al. ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells. FEBS Lett 2001;508:221–5.
Garmany TH, Moxley MA, White FV, et al. Surfactant composition and function in patients with ABCA3 mutations. Pediatr Res 2006;59:801–5.
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M . ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 2004;350:1296–303.
Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM . ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 2005;172:1026–31.
Karjalainen MK, Haataja R, Hallman M . Haplotype analysis of ABCA3: association with respiratory distress in very premature infants. Ann Med 2008;40:56–65.
Garmany TH, Wambach JA, Heins HB, et al. Population and disease-based prevalence of the common mutations associated with surfactant deficiency. Pediatr Res 2008;63:645–9.
Hamvas A, Cole FS, Nogee LM . Genetic disorders of surfactant proteins. Neonatology 2007;91:311–7.
Bækvad-Hansen M, Nordestgaard BG, Dahl M . Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals. Respir Res 2012;13:67.
Wambach JA, Wegner DJ, Depass K, et al. Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics 2012;130:e1575–82.
Hammel M, Michel G, Hoefer C, et al. Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies. Biochem Biophys Res Commun 2007;359:947–51.
Fitzgerald ML, Xavier R, Haley KJ, et al. ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol. J Lipid Res 2007;48:621–32.
Cheong N, Zhang H, Madesh M, et al. ABCA3 is critical for lamellar body biogenesis in vivo. J Biol Chem 2007;282:23811–7.
Tokieda K, Iwamoto HS, Bachurski C, et al. Surfactant protein-B-deficient mice are susceptible to hyperoxic lung injury. Am J Respir Cell Mol Biol 1999;21:463–72.
Smith LJ . Hyperoxic lung injury: biochemical, cellular, and morphologic characterization in the mouse. J Lab Clin Med 1985;106:269–78.
Crapo JD . Morphologic changes in pulmonary oxygen toxicity. Annu Rev Physiol 1986;48:721–31.
dos Santos CC, Slutsky AS . The contribution of biophysical lung injury to the development of biotrauma. Annu Rev Physiol 2006;68:585–618.
Veldhuizen EJ, Haagsman HP . Role of pulmonary surfactant components in surface film formation and dynamics. Biochim Biophys Acta 2000;1467:255–70.
Hite RD, Seeds MC, Bowton DL, et al. Surfactant phospholipid changes after antigen challenge: a role for phosphatidylglycerol in dysfunction. Am J Physiol Lung Cell Mol Physiol 2005;288:L610–7.
Tschumperlin DJ, Drazen JM . Chronic effects of mechanical force on airways. Annu Rev Physiol 2006;68:563–83.
Zemans RL, Matthay MA . Bench-to-bedside review: the role of the alveolar epithelium in the resolution of pulmonary edema in acute lung injury. Crit Care 2004;8:469–77.
Besnard V, Matsuzaki Y, Clark J, et al. Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice. Am J Physiol Lung Cell Mol Physiol 2010;298:L646–59.
Riley DJ, Kramer MJ, Kerr JS, Chae CU, Yu SY, Berg RA . Damage and repair of lung connective tissue in rats exposed to toxic levels of oxygen. Am Rev Respir Dis 1987;135:441–7.
Xu Y, Saegusa C, Schehr A, Grant S, Whitsett JA, Ikegami M . C/EBP{alpha} is required for pulmonary cytoprotection during hyperoxia. Am J Physiol Lung Cell Mol Physiol 2009;297:L286–98.
Brasch F, Schimanski S, Mühlfeld C, et al. Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am J Respir Crit Care Med 2006;174:571–80.
Bullard JE, Nogee LM . Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation. Pediatr Res 2007;62:176–9.
Mahavadi P, Korfei M, Henneke I, et al. Epithelial stress and apoptosis underlie Hermansky-Pudlak syndrome-associated interstitial pneumonia. Am J Respir Crit Care Med 2010;182:207–19.
Liebisch G, Lieser B, Rathenberg J, Drobnik W, Schmitz G . High-throughput quantification of phosphatidylcholine and sphingomyelin by electrospray ionization tandem mass spectrometry coupled with isotope correction algorithm. Biochim Biophys Acta 2004;1686:108–17.
Leidl K, Liebisch G, Richter D, Schmitz G . Mass spectrometric analysis of lipid species of human circulating blood cells. Biochim Biophys Acta 2008;1781:655–64.
Brügger B, Erben G, Sandhoff R, Wieland FT, Lehmann WD . Quantitative analysis of biological membrane lipids at the low picomole level by nano-electrospray ionization tandem mass spectrometry. Proc Natl Acad Sci USA 1997;94:2339–44.
Matyash V, Liebisch G, Kurzchalia TV, Shevchenko A, Schwudke D . Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J Lipid Res 2008;49:1137–46.
Flemmer AW, Jani JC, Bergmann F, et al. Lung tissue mechanics predict lung hypoplasia in a rabbit model for congenital diaphragmatic hernia. Pediatr Pulmonol 2007;42:505–12.
Lovgren AK, Jania LA, Hartney JM, et al. COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2006;291:L144–56.
Bates JH . Understanding lung tissue mechanics in terms of mathematical models. Monaldi Arch Chest Dis 1993;48:134–9.
Hantos Z, Daróczy B, Suki B, Nagy S, Fredberg JJ . Input impedance and peripheral inhomogeneity of dog lungs. J Appl Physiol 1992;72:168–78.
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Herber-Jonat, S., Mittal, R., Huppmann, M. et al. Abca3 haploinsufficiency is a risk factor for lung injury induced by hyperoxia or mechanical ventilation in a murine model. Pediatr Res 74, 384–392 (2013). https://doi.org/10.1038/pr.2013.127
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DOI: https://doi.org/10.1038/pr.2013.127
