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(American Journal of Pathology. 2000;156:1407-1416.)
© 2000 American Society for Investigative Pathology

Regular Articles

Cystic Fibrosis Transmembrane Conductance Regulator Does Not Affect Neutrophil Migration across Cystic Fibrosis Airway Epithelial Monolayers

Lara Pizurki^*, Michael A. Morris, Marc Chanson^*, Melete Solomon^*, Andrea Pavirani, Isabelle Bouchardy and Susanne Suter^*

From the Laboratory of Clinical Investigation III,^*
Department of Pediatrics, University Hospitals, Geneva, Switzerland; the Division of Medical Genetics,
University Medical School, Geneva, Switzerland; and Transgène SA,
Strasbourg, France

Recent studies have shown that airway inflammation dominated by neutrophils, ie, polymorphonuclear cells (PMN) was observed in infants and children with cystic fibrosis (CF) even in the absence of detectable infection. To assess whether there is a CF-related anomaly of PMN migration across airway epithelial cells, we developed an in vitro model of chemotactic migration across tight and polarized CF₁₅ cells, a CF human nasal epithelial cell line, seeded on porous filters. To compare PMN migration across a pair of CF and control monolayers in the physiological direction, inverted CF₁₅ cells were infected with increasing concentrations of recombinant adenoviruses containing either the normal cystic fibrosis transmembrane conductance regulator (CFTR) cDNA, the F508 CFTR cDNA, or the ß-galactosidase gene. The number of PMN migrating in response to N-formyl-Met-Leu-Phe across inverted CF₁₅ monolayers expressing ß-galactosidase was similar to that seen across CF₁₅ monolayers rescued with CFTR, whatever the proportion of cells expressing the transgene. Moreover, PMN migration across monolayers expressing various amounts of mutated CFTR was not different from that observed across matched counterparts expressing normal CFTR. Finally, PMN migration in response to adherent or Pseudomonas aeruginosa was equivalent across CF and corrected monolayers. The possibility that mutated CFTR may exert indirect effects on PMN recruitment, via an abnormal production of the chemotactic cytokine interleukin-8, was also explored. Apical and basolateral production of interleukin-8 by polarized CF cells expressing mutated CFTR was not different from that observed with rescued cells, either in baseline or stimulated conditions. CF₁₅ cells displayed a CF phenotype that could be corrected by CFTR-containing adenoviruses, because two known CF defects, Cl^- secretion and increased P. aeruginosa adherence, were normalized after infection with those viruses. Thus, we conclude that the presence of a mutated CFTR does not per se lead to an exaggerated inflammatory response of CF surface epithelial cells in the absence or presence of a bacterial infection.

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