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Hypoxia Increases Corneal Cell Expression of CFTR Leading to Increased Pseudomonas aeruginosa Binding, Internalization, and Initiation of Inflammation

¹From the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and ²CIBA Vision Corporation, Division of Novartis, Duluth, Georgia.

PURPOSE. To investigate the effect of hypoxia-induced molecular responses of corneal epithelial cells on the surface of rabbit and human corneas and corneal cells in culture on interactions with Pseudomonas aeruginosa that may underlie increased susceptibility to keratitis.

METHODS. Organ cultures of rabbit and human corneal tissue, primary rabbit and human corneal cells, and transformed human corneal cells from a patient with cystic fibrosis and the same cell line corrected for expression of wild-type cystic fibrosis transmembrane conductance regulator (CFTR), the cellular receptor for P. aeruginosa, were exposed to hypoxic conditions for 24 to 72 hours. Changes in binding and internalization of P. aeruginosa were measured using cellular association and gentamicin-exclusion assays, and expression of CFTR and activation of NF-B in response to hypoxia were determined by confocal laser microscopy and quantitative measurements of NF-B activation.

RESULTS. Hypoxia induced in a time- and oxygen-concentration–dependent manner increased association and internalization of clinical isolates of P. aeruginosa in all cells tested. Hypoxia increased CFTR expression and NF-B nuclear translocation in rabbit and human cells with wild-type CFTR. Corneal cells lacking CFTR had reduced NF-B activation in response to hypoxia. Hypoxia did not affect the increase in corneal cell CFTR levels or NF-B activation after P. aeruginosa infection.

CONCLUSIONS. Hypoxic conditions on the cornea exacerbate the binding and internalization of P. aeruginosa due to increased levels of CFTR expression and also induce basal NF-B activation. Both of these responses probably exacerbate the effects of P. aeruginosa infection by allowing lower infectious doses of bacteria to induce disease and promote destructive inflammatory responses.

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