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Effects of hyperoxia on transdifferentiation of primary cultured typeII alveolar epithelial cells from premature rats

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Abstract

Hyperoxia exposure is a significant risk factor for the impaired alveolarization characteristic of bronchopulmonary dysplasia. Type II alveolar epithelial cells (AECIIs) may serve as “alveolar stem cells” to transdifferentiate into type I alveolar epithelial cells (AECIs). Here, we show that hyperoxia is capable of inducing transdifferentiation of AECIIs in premature rats in vitro. Hyperoxia-induced transdifferentiation was characterized by typical morphological changes, inhibition of cellular proliferation, decline in expression rate of Ki67, accumulation of cells in the G1 phase of the cell cycle, increased expression of AECI-specific protein aquaporin 5, and decreased expression of AECII-associated protein surfactant protein C. These results suggest that hyperoxia may induce transdifferentiation of AECIIs into AECIs and the transdifferentiation may be responsible for repairing early lung injury.

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References

  • Adamson I. Y.; Bowden D. H. The type 2 cells as progenitor of alveolar epithelium regeneration. A cytodynamic study of mice after exposure to oxygen. Lab. Invest. 30: 35–42; 1974.

    CAS  PubMed  Google Scholar 

  • Barker G. F.; Manzo N. D.; Cotich K. L.; Shone R. K.; Waxman A. B. DNA damage induced by hyperoxia: quantitation and correlation with lung injury. Am. J. Respir. Cell Mol. Biol. 35: 277–288; 2006.

    Article  CAS  PubMed  Google Scholar 

  • Bishop A. E. Pulmonary epithelial stem cells. Cell Prolif. 37: 89–96; 2004.

    Article  CAS  PubMed  Google Scholar 

  • Borok Z.; Lubman R. L.; Danto S. I.; Zhang X. L.; Zabski S. M.; King L. S.; Lee D. M.; Agre P.; Crandall E. D. Keratinocyte growth factor modulates alveolar epithelial cell phenotype in vitro: expression of aquaporin 5. Am. J. Respir. Cell Mol. Biol. 18: 554–561; 1998.

    CAS  PubMed  Google Scholar 

  • Bourbon J.; Boucherat O.; Chailley-Heu B.; Delacourt C. Control mechanisms of lung alveolar development and their disorders in bronchopulmonary dysplasia. Pediatr. Res. 57: 38R–46R; 2005.

    Article  PubMed  Google Scholar 

  • Campbell L.; Hollins A. J.; Al-Eid A.; Newman G. R.; von Ruhland C.; Gumbleton M. Caveolin-1 expression and caveolae biogenesis during cell transdifferentiation in lung alveolar epithelial primary cultures. Biochem. Biophys. Res. Commun. 262: 744–751; 1999.

    Article  CAS  PubMed  Google Scholar 

  • Cao Y. X.; Ramirez M. I.; Williams M. C. Enhanced binding of Sp1/Sp3 transcription factors mediates the hyperoxia-induced increased expression of the lung type I cell gene T1 alpha. J. Cell Biochem. 89: 887–901; 2003.

    Article  CAS  PubMed  Google Scholar 

  • Choo-Wing R.; Nedrelow J. H.; Homer R. J.; Elias J. A.; Bhandari V. Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia. Am. J. Physiol. Lung Cell Mol. Physiol. 293: L142–L150; 2007.

    Article  CAS  PubMed  Google Scholar 

  • Crapo J. D.; Barry B. E.; Gehr P.; Bachofen M.; Weibel E. R. Cell number and cell characteristics of normal human lung. Am. Rev. Respir. Dis. 126: 332–337; 1982.

    CAS  PubMed  Google Scholar 

  • Danto S. I.; Shannon J. M.; Borok Z.; Zabski S. M.; Crandall E. D. Reversible transdifferentiation of alveolar epithelial cells. Am. J. Respir. Cell Mol. Biol. 12: 497–502; 1995.

    CAS  PubMed  Google Scholar 

  • Dasgupta C.; Sakurai R.; Wang Y.; Guo P.; Ambalavanan N.; Torday J. S.; Rehan V. K. Hyperoxia-induced neonatal rat lung injury involves activation of TGF-{beta} and Wnt signaling and is protected by rosiglitazone. Am. J. Physiol. Lung Cell Mol. Physiol. 296: L1031–1041; 2009.

    Article  CAS  PubMed  Google Scholar 

  • Dauger S.; Ferkdadji L.; Saumon G.; Vardon G.; Peuchmaur M.; Gaultier C.; Gallego J. Neonatal exposure to 65% oxygen durably impairs lung architecture and breathing pattern in adult mice. Chest 123: 530–538; 2003.

    Article  PubMed  Google Scholar 

  • Fehrenbach H. Alveolar epithelial type II cell: defender of the alveolus revisited. Respir. Res. 2: 33–46; 2001.

    Article  CAS  PubMed  Google Scholar 

  • Gehen S. C.; Vitiello P. F.; Bambara R. A.; Keng P. C.; O’Reilly M. A. Downregulation of PCNA potentiates p21-mediated growth inhibition in response to hyperoxia. Am. J. Physiol. Lung Cell Mol. Physiol. 292: L716–724; 2007.

    Article  CAS  PubMed  Google Scholar 

  • Gomi T.; Kimura A.; Adriaensen D.; Timmermans J. P.; Scheuermann D. W.; DeGroodt-Lasseel M. H.; Kitazawa Y.; Kikuchi Y.; Naruse H.; Kishi K. Stages in the development of the rat lung: morphometric, light and electron microscopic studies. Kaibogaku Zasshi 69: 392–405; 1994.

    CAS  PubMed  Google Scholar 

  • Lee J.; Reddy R.; Barsky L.; Weinberg K.; Driscoll B. Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia. Am. J. Physiol. Lung Cell Mol. Physiol. 290: 685–694; 2006.

    Article  Google Scholar 

  • Mason R. J.; Kalina M.; Nielsen L. D.; Malkinson A. M.; Shannon J. M. Surfactant protein C expression in urethane-induced murine pulmonary tumors. Am. J. Pathol. 156: 175–182; 2000.

    CAS  PubMed  Google Scholar 

  • McGrath-Morrow S. A.; Stahl J. Growth arrest in A549 cells during hyperoxic stress is associated with decreased cyclin B1 and increased P21(Wafl/Cipl/Sdi1) levels. Biochim. Biophys. Acta. 1538: 90–97; 2001.

    Article  CAS  PubMed  Google Scholar 

  • Nielsen S.; King L. S.; Christensen B. M.; Agre P. Aquaporins in complex tissue: II. Subcellular distribution in respiratory and glandular tissues of rat. Am. J. Physiol. 273: 1549–1561; 1997.

    Google Scholar 

  • Rancourt R. C.; Hayes D. D.; Chess P. R.; Keng P. C.; O’Reilly M. A. Growth arrest in G1 protects against oxygen-induced DNA damage and cell death. J. Cell Physiol. 193: 26–36; 2002.

    Article  CAS  PubMed  Google Scholar 

  • Rancourt R. C.; Keng P. C.; Helt C. E.; O’Reilly M. A. The role of p21 (CIP1/WAF1) in growth of epithelial cells exposed to hyperoxia. Am. J. Physiol. Lung Cell Mol. Physiol. 280: 617–626; 2001.

    Google Scholar 

  • Scholzen T.; Gerdes J. The Ki-67 protein: from the known and the unknown. J. Cell Physiol. 182: 311–322; 2000.

    Article  CAS  PubMed  Google Scholar 

  • Takeyama N.; Matsuo N.; Tanaka T. Oxidative damage to mitochondria is mediated by the Ca(2+)-dependent inner-membrane permeability transition. Biochem. J. 294: 719–725; 1993.

    CAS  PubMed  Google Scholar 

  • Wang H.; Chang L. W.; Li W. B. Temporal expression of Notch in preterm rat lungs exposed to hyperoxia. J. Huazhong Univ. Sci. Technolog. Med. Sci. 25: 159–161; 2005.

    Article  PubMed  Google Scholar 

  • Watanabe N.; Dickinson D. A.; Krzywanski D. M.; Iles K. E.; Zhang H.; Venglarik C. J.; Forman H. J. A549 subclones demonstrate heterogeneity in toxicological sensitivity and antioxidant profile. Am. J. Physiol. Lung Cell Mol. Physiol. 283: 726–736; 2002.

    Google Scholar 

  • Woyda K.; Koebrich S.; Reiss I.; Rudloff S.; Pullamsetti S. S.; Ruhlmann A.; Weissmann N.; Gunther A.; Seeger W.; Grimminger F.; Morty R. E.; Schermuly R. T. Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia. Eur. Respir. J. 33: 861–870; 2009.

    Article  CAS  PubMed  Google Scholar 

  • Yee M.; Vitiello P. F.; Roper J. M.; Staversky R. J.; Wright T. W.; McGrath-Morrow S. A.; Maniscalco W. M.; Finkelstein J. N.; O’Reilly M. A. Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development. Am. J. Physiol. Lung Cell Mol. Physiol. 291: L1101–1111; 2006.

    Article  CAS  PubMed  Google Scholar 

  • Zhu H. P.; Chang L. W.; Li W. B.; Liu H. C.; Zhang Q. S. Isolation and purification and primary culture of lung cells from fetal rat lung. J. Huazhong Univ. Sci. Technolog. Med. Sci. 32: 597–600; 2003.

    Google Scholar 

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Acknowledgements

We gratefully acknowledge support for this project provided by Prof. Liwen Chang and funded by the National Nature Science foundation of China (No. 30471824).

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Correspondence to Hong-Yan Lu.

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Editor: J. Denry Sato

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Lu, HY., Shao, GB., Li, WB. et al. Effects of hyperoxia on transdifferentiation of primary cultured typeII alveolar epithelial cells from premature rats. In Vitro Cell.Dev.Biol.-Animal 47, 64–72 (2011). https://doi.org/10.1007/s11626-010-9360-9

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  • DOI: https://doi.org/10.1007/s11626-010-9360-9

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