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Volume 272, Number 44, Issue of October 31, 1997 pp. 27830-27838
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

ATP Depletion Induces a Loss of Respiratory Epithelium Functional Integrity and Down-regulates CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) Expression

(Received for publication, March 5, 1997, and in revised form, August 23, 1997)

Stéphane Brézillon , Jean-Marie Zahm , Denis Pierrot , Dominique Gaillard , Jocelyne Hinnrasky , Hervé Millart ^§ , Jean-Michel Klossek ^¶ , Burkhard Tümmler and Edith Puchelle

From  INSERM Unité 314, IFR 53, Université de Reims, 51092 Reims cedex, France, ^§ Laboratoire de Pharmacologie-Toxicologie, IFR 53, Centre Hospitalier Universitaire Maison Blanche, 51092 Reims cedex, France, ^¶ Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, Centre Hospitalier Universitaire Jean Bernard, 86021 Poitiers cedex, France, and  Klinische Forschergruppe, D30623 Hannover, Germany

To mimic the effect of ischemia on the integrity of airway epithelium and expression of cystic fibrosis transmembrane conductance regulator (CFTR), we induced an ATP depletion of the respiratory epithelium from upper airway cells (nasal tissue) and human bronchial epithelial 16HBE14o cell line. Histological analysis showed that 2 h of ATP depletion led to a loss of the epithelium integrity at the interface between basal cells and columnar cells. The expression of connexin 43 (Cx43, subunit of the gap junctions) and desmoplakins 1 and 2 (DPs 1 and 2, major components of the desmosomes) proteins was inhibited. After 90 min of ATP depletion, a significant decrease of the transepithelial resistance (25%) was observed but was reversible. Similar results were obtained with the 16HBE14o human bronchial epithelial cell line. ATP depletion led to actin filaments depolymerization. The expression of the mature CFTR (170 kDa) and fodrin proteins at the apical domain of the ciliated cells was down-regulated. The steady-state levels of CFTR, Cx43, DPs 1 and 2 mRNAs, semiquantified by RT-polymerase chain reaction kinetics, remained constant throughout ATP depletion in nasal tissue as in the homogeneous cell population of 16HBE14o human bronchial epithelial cell line. This suggests that the down-regulation of these proteins might be posttranscriptional. The intercellular diffusion through gap junctions of Lucifer dye was completely inhibited after 90 min of ATP depletion but was reversible. The volume-dependent and the cAMP-dependent chloride secretion were inhibited in a nonreversible way. Taken together, these results suggest that an ATP depletion in human airway epithelium, mimicking ischemia, may induce a marked alteration in the junctional complexes and cytoskeleton structure concomitantly with a loss of apical CFTR expression and chloride secretion function.

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