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Inhibition of CLC-2 chloride channel expression interrupts expansion of fetal lung cysts

Departments of ¹Pediatrics and ²Physiology, University of Maryland, Baltimore, Maryland 21201; and ³Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil

Submitted 4 April 2003 ; accepted in final form 30 October 2003

Normal lung morphogenesis is dependent on chloride-driven fluid transport. The molecular identity of essential fetal lung chloride channel(s) has not been elucidated. CLC-2 is a chloride channel, which is expressed on the apical surface of the developing respiratory epithelium. CLC-2-like pH-dependent chloride secretion exists in fetal airway cells. We used a 14-day fetal rat lung submersion culture model to examine the role of CLC-2 in lung development. In this model, the excised fetal lung continues to grow, secrete fluid, and become progressively cystic in morphology (26). We inhibited CLC-2 expression in these explants, using antisense oligonucleotides, and found that lung cyst morphology was disrupted. In addition, transepithelial voltage (V_t) of lung explants transfected with antisense CLC-2 was inhibited with V_t = -1.5 ± 0.2 mV (means + SE) compared with -3.7 ± 0.3 mV (means + SE) for mock-transfected controls and -3.3 ± 0.3 mV (means + SE) for nonsense oligodeoxynucleotide-transfected controls. This suggests that CLC-2 is important for fetal lung fluid production and that it may play a role in normal lung morphogenesis.

lung development; chloride secretion

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