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Published ahead of print on May 11, 2006, doi:10.1165/rcmb.2005-0251OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 4, October 2006, 424-435

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Submitted on July 8, 2005
Revised on May 11, 2006

Gene Expression Profile of Human Airway Epithelium Induced by Hyperoxia In Vivo

Arnaud Chambellan1, Paul J Cruickshank2, Patrick McKenzie2, Steven B Cannady3, Katalin Szabo2, Suzy A.A. Comhair2, and Serpil C Erzurum4*

1 Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, OH, USA; Faculte de Medecine, INSERM U 533, Institut du Thorax, Nantes, France, 2 Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, OH, USA, 3 Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, OH, USA; The Cleveland Clinic Foundation, The Head and Neck Institute, Cleveland, OH, USA, 4 Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, OH, USA; Departments of Pulmonary, Allergy and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, OH, USA

* To whom correspondence should be addressed. E-mail: erzurus{at}ccf.org.

Hyperoxia leads to oxidative modification and damage of macromolecules in the respiratory tract with loss of biological functions. Given the lack of antioxidant gene induction with acute exposure to 100% oxygen, we hypothesized that clearance pathways for oxidatively modified proteins may be induced and serve in the immediate cellular response to preserve the epithelial layer. To test this, airway epithelial cells were obtained from individuals under ambient oxygen conditions and after breathing 100% oxygen for 12 hours. Gene expression profiling identified induction of genes in the chaperone and proteasome-ubiquitin-conjugation pathways that together comprise an integrated cellular response to manage and degrade damaged proteins. Analyses also revealed gene expression changes associated with oxidoreductase function, cell cycle regulation, and ATP synthesis. Increased HSP70, protein ubiquitination and intracellular ATP were validated in cells exposed to hyperoxia in vitro. Inhibition of proteasomal degradation revealed the importance of accelerated protein catabolism for energy production of cells exposed to hyperoxia. Thus, the human airway early response to hyperoxia relies predominantly upon induction of cytoprotective chaperones and the ubiquitin-proteasome-dependent protein degradation system to maintain airway homeostatic integrity.






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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
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