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An Extract from the Medicinal Plant Phyllanthus acidus and Its Isolated Compounds Induce Airway Chloride Secretion: A Potential Treatment for Cystic Fibrosis

Institut für Physiologie, Universität Regensburg, Regensburg, Germany (J.O., R.S., S.P., R.S., K.K.); Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisboa and Centre of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal (M.S., A.R., A.S., T.G., M.D.A.); and Department of Physiology, Prince of Songkla University, Hat-Yai, Thailand (C.J.)

According to previous reports, flavonoids and nutraceuticals correct defective electrolyte transport in cystic fibrosis (CF) airways. Traditional medicinal plants from China and Thailand contain phytoflavonoids and other bioactive compounds. We examined herbal extracts of the common Thai medicinal euphorbiaceous plant Phyllanthus acidus for their potential effects on epithelial transport. Functional assays by Ussing chamber, patch-clamping, double-electrode voltage-clamp and Ca²⁺ imaging demonstrate activation of Cl^- secretion and inhibition of Na⁺ absorption by P. acidus. No cytotoxic effects of P. acidus could be detected. Mucosal application of P. acidus to native mouse trachea suggested transient and steady-state activation of Cl^- secretion by increasing both intracellular Ca²⁺ and cAMP. These effects were mimicked by a mix of the isolated components adenosine, kaempferol, and hypogallic acid. Additional experiments in human airway cells and CF transmembrane conductance regulator (CFTR)-expressing BHK cells and Xenopus laevis oocytes confirm the results obtained in native tissues. Cl^- secretion was also induced in tracheas of CF mice homozygous for Phe508del-CFTR and in Phe508del-CFTR homozygous human airway epithelial cells. Taken together, P. acidus corrects defective electrolyte transport in CF airways by parallel mechanisms including 1) increasing the intracellular levels of second messengers cAMP and Ca²⁺, thereby activating Ca²⁺-dependent Cl^- channels and residual CFTR-Cl^- conductance; 2) stimulating basolateral K⁺ channels; 3) redistributing cellular localization of CFTR; 4) directly activating CFTR; and 5) inhibiting ENaC through activation of CFTR. These combinatorial effects on epithelial transport may provide a novel complementary nutraceutical treatment for the CF lung disease.

Address correspondence to: Prof. Dr. Karl Kunzelmann, Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. E-mail: uqkkunze{at}mailbox.uq.edu.au