Modulating macrophage-mediated Inflammation in cystic fibrosis

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ABSTRACT Dr. Katherine Hisert's research is focused on understanding the role of macrophages in chronic inflammatory lung diseases. Her long term goal is to become an independent physician scientist engaged in clinical practice and translational research, with a focus on the disease cystic fibrosis (CF). To achieve this goal, Dr. Hisert has defined a comprehensive career development program that builds on her prior training in basic immunology research, including continued development of her clinical skills in the UW Adult CF clinic, and instruction in computational skills for analysis of large datasets generated by “omics” technologies. This training will enable successful execution of the proposed studies, and prepare Dr. Hisert for a career in which she can perform true bench to bedside research. This research proposal investigates the potential use of a novel anti-inflammatory medication, gallium nitrate, to improve disease outcomes by suppressing pro-inflammatory macrophage responses. In a prior phase 1b clinical trial, gallium improved lung function in CF patients with chronic bacterial airway infections, but whether gallium's therapeutic effect was due to its anti- microbial properties or to anti-inflammatory properties was unclear. Dr. Hisert will test the hypothesis that gallium reduces LPS- and bacterially mediated lung injury by suppressing pro- inflammatory macrophage functions, and decreases airway inflammation in CF patients with chronic infections. Aim 1 will determine which macrophage functions are altered by gallium, and investigate the molecular mechanisms by which gallium attenuates macrophage inflammatory responses. Aim 2 will use murine models to test if gallium protects against LPS-mediated lung injury by suppressing pro-inflammatory macrophage responses in vivo. Aim 3 will take advantage of a phase II clinical trial testing IV gallium's ability to improve lung function in CF patients with chronic Pseudomonas infections. Dr. Hisert will isolate sputum macrophages before and after patients receive IV gallium and investigate whether suppression of macrophage pro-inflammatory gene expression is associated with improved lung function. Together these studies will lead to a better understanding of gallium's anti-inflammatory effects, and explore the possibility that suppressing pro-inflammatory macrophage functions could be therapeutic in CF, and possibly other chronic inflammatory diseases.