Plant-derived Auxins as Inhibitors of Neutrophil Myeloperoxidase: Potential Therapeutic Agents for the Treatment of Cystic Fibrosis

Cystic Fibrosis (CF) is a hereditary disease that results in the accumulation of viscous mucus in the lung. As a result, CF patients suffer chronic infections, overwhelming inflammation and oxidative stress that leads to pulmonary dysfunction and ultimately premature death. Chronic inflammation in the CF lung is associated with exuberant recruitment of neutrophils into the CF airway. Neutrophils express the highly abundant hemeoprotein/enzyme myeloperoxidease (MPO) that can cause oxidative injury in the CF airway via the production of reactive oxidants such as hypochlorous acid (HOCl; otherwise known as ‘bleach’). Under pathological conditions the hyperactivation of MPO can cause injury to airway epithelial cells and the levels of this enzyme are positively associated with decreased lung function in CF. We have hypothesized that MPO may be a feasible therapeutic target for the treatment of CF. A survey of natural chemicals possessing an indole moiety reveal plant-based compounds typically termed ‘auxins’ as potential inhibitors of MPO. Accordingly, we have begun to test a number of these indole derivatives as MPO inhibitors such as indole-3-carbinol, indole-3-carboxylic acid, indole-3-acetic acid and indole-3-propionic acid. Spectrophotometric assays have been utilized to assess the ability of these compounds to inhibit MPO.  While preliminary results indicate the potential for these compounds to inhibit MPO, more studies are necessary. Successful completion of these studies will define the capacity of these natural products, either through dietary means or in pure form, to be utilized as therapeutic agents to ameliorate oxidative stress and inflammation in CF and related lung diseases.