and mucus hypersecretion in diseased airways chronically colonized by PA is likely a cumulative effect of ROS RNS mediated posttranslational modification of FOXA2 and the activation of IL 4 IL 13 STAT6 and EGFR signaling pathways http://www.selleckchem.com/products/Gefitinib.html that inhibit the expression of FOXA2. However, excessive levels of PCN generated ROS RNS may potentially impair the function of com ponents of Stat6 and EGFR pathways. Thus, it is likely that PCN mediated repression of FOXA2 is a bigger contributor of GCHM and mucus hypersecretion than the partial loss of function for both Stat6 and EGFR sig naling components. Future studies will address these matters in more detail. Thiol compounds, including GSH, are known to play important roles in pulmonary diseases. One study in rats has shown that the concentration of lung GSH is approximately 2 mM.

GSH at concentrations as high as 10 mM has been used in cell culture Inhibitors,Modulators,Libraries experi ments. Importantly, inhaled GSH therapy has been shown to improve the lung function of CF patients, as well as liquefy the mucus. Our results provide a possible mechanistic basis for the beneficial treatment with thiols. For example, GSH at physiologically relevant concentrations of 0. 4 2. 5 mM not only reduces the production of PCN generated ROS RNS, it also attenu ates the posttranslational modifications and inactivation of FOXA2, and, in the process, suppresses the produc tion of excessive mucins. Collectively, our experimental results suggest that providing physiologically relevant con centrations of GSH can counter the induction of GCHM by clinically relevant concentrations of PCN.

Future studies will examine the efficacy of GSH against GCHM and mucus hypersecretion mediated by PCN in mouse airways, as well as during infection by wild type versus PCN deficient laboratory and clinical strains of PA. One surprising finding from our studies is the robust mucin secretion induced by PCN in the polarized NHBE cells. Inhibitors,Modulators,Libraries At a clinically relevant concentration of 12. 5 ug ml, PCN induces higher levels of MUC5AC expression than IL 13 after 24 hr of exposure in NHBE cells. Similarly, PCN also induces substantial Inhibitors,Modulators,Libraries expression Inhibitors,Modulators,Libraries of MUC5B mucin in the polarized NHBE cells. Interestingly, induction of mucin secretion with short exposure to IL 13 has not been reported. One potential discrepancy between the current study and other reports lies in the IL 13 concentration used.

We exposed NHBE cells to 1 ug ml of recombinant human IL 13 and probed for mucin expression at 24 hr whereas other stud ies used 10 ng ml over 7 14 days to induce differentiation of mucous Carfilzomib cells and increases in MUC5AC protein. However, there have been other short duration studies that http://www.selleckchem.com/products/VX-770.html used higher concentrations of IL 13 to induce GCHM and mucin expression. For example, instillation of mouse recombinant IL 13 has been shown to induce GCHM and mucin overexpression within mouse airways. Thus, our current study resembles the studies that used higher amounts of IL 13 in short dur ation of exposure. We acknowled