William Zhengyang Zhang, MD

The long-term goal of our laboratory is to understand the role of iron metabolism in chronic obstructive pulmonary disease (COPD) pathogenesis. We recently demonstrated using a multicenter prospective COPD cohort that elevated iron levels in the bronchoalveolar lavage fluid of smokers and COPD patients associate with negative clinical outcomes, including exacerbation frequency. We hypothesize that this increase in iron comes from iron-overloaded alveolar macrophages in these patients, and it is the objective of this proposal to examine the mechanism behind this abnormal macrophage iron accumulation. Using a murine cigarette smoke exposure model, our preliminary results show that a subset of alveolar macrophages from mice exposed to smoke upregulates genes associated with iron metabolism and uptake, and that this gene expression profile is associated with decreased expression of other important genes that characterize alveolar macrophage function and identity. We leveraged these gene expression findings and developed a flow cytometric method to isolate these iron-dysregulated alveolar macrophages using an iron surface protein as a marker, and are currently working toward performing functional assays on this subset of cells. We have also developed a murine knockout model in which a disruption in a critical iron metabolism pathway prevents smoke-induced accumulation in alveolar macrophages, and we are in the progress of assessing the biological implications this iron unloading has on macrophage function in response to smoke and in the setting of infection. Finally, we have obtained freshly harvested alveolar macrophages from healthy volunteers and smokers with and without COPD and are examining our hypothesis by treating these cells with agents such as iron chelators to specifically target iron. Ultimately, our goal is to translate our results at the bench to the bedside and develop a therapy that is directed at iron metabolism for COPD patients. Despite the progress that has been made in COPD research, there is still no pharmacologic therapy that has been shown to alter the trajectory of disease in COPD patients. Given the role of alveolar macrophages in host defense, we believe that they are important targets in COPD treatment. Our preliminary results from this first year confirm our hypothesis that iron loading in alveolar macrophages is not merely an epiphenomenon in COPD, and we look forward to extending on these findings on functional and mechanistic levels in the next year.

Update: The long-term goal of our laboratory is to understand the role of iron metabolism in the pathogenesis of chronic obstructive pulmonary disease (COPD). This proposal focuses on alveolar macrophages, sentinel immune cells in the airways which abnormally accumulate iron in COPD. Our research plan investigates the mechanisms and biological implications of this iron overload phenomenon using both disease models and alveolar macrophage collected from COPD patients. Our preliminary results suggest that abnormal iron homeostasis in alveolar macrophage is linked to their dysfunction, and additional work is ongoing to examine whether correcting this iron dysregulation can curtail COPD development.