Plant extracts and isolated compounds for therapy of cystic fibrosis

The analysis of the effects of extracts from medicinal plants is one of the most interesting approaches for the identification of bioactive compounds to be used in the treatment of human pathologies. Cystic Fibrosis is a severe genetic disease due to defects of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF affects several organs with the chronic pulmonary disease being the major cause of reduction of the quality and expectancy of life. Hallmark of CF lung disease is in most cases the chronic infection sustained by the gram negative bacterium Pseudomonas aeruginosa and the excessive lung inflammation with a huge infiltrate of eutrophils in the bronchial lumen, mainly due to the release of the chemokine interleukin (IL)-8. Accordingly, the identification of novel drugs able to reduce the excessive lung inflammation in CF is considered one of the key therapeutic targets to circumvent progressive lung tissue deterioration. Since, NF-kB is involved in the transcriptional regulation of IL-8 gene we screened plant extracts from Lebanon, China, Pakistan, Bangladesh, Egypt for NF-kB inhibition. Then, we tried to identify bioactive compounds. A first example is Phyllanthus urinaria which has been demonstrated to inhibit NF-kB; analysis of the chemical composition allowed to identify rilagin and the bioactive compound (1). A second example is resveratrol, present in Japanese knotweed Polygonum cuspidatum and in red grape skins. In this case resveratrol was found to exert antibacterial activity on and inhibitory effects on IL-8 gene expression (2). A third example is Aegle marmelos and Emblica officinalis extracts, which were found to inhibit NF-kB/DNA interactions. 5-methoxysoralen (Aegle marmelos) (3) and pyrogallol (Emblica officinalis) (4) were found as the bioactive compound responsible for inhibition of IL-8 in cystic fibrosis cells infected with Pseudomonas aeruginosa. A 5-methoxypsoralen analogue, 4,6,4'-trimethylangelicin (TMA), was found to inhibit P. aeruginosa-dependent IL-8 transcription at nanomolar concentration in IB3-1, CuFi-1, CFBE41o-, and Calu-3 bronchial epithelial cell lines without exhibiting antibacterial activity. Since psoralens have been shown to potentiate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride transport, TMA was tested and found to potentiate CFTR-dependent chloride efflux (5). Taken together, these studies support the concept that plant extracts contain bioactive compounds of possible interest to develop anti-inflammatory protocols for cystic fibrosis.