Inflammatory Injury Caused by Silica Exposure

Project Summary More than 2 million people in the US are exposed to respirable crystalline silica at work. Inhalation of dust containing respirable crystalline silica causes silicosis, which is characterized by chronic inflammation and pulmonary fibrosis. Silica exposure also increases the risk of developing autoimmune diseases and cancer. Silicosis patients have a median survival of 6 years after diagnosis. The pathophysiology of silicosis has not been fully understood. Currently, there is no effective treatment against this devastating disease. It has been reported that the dysregulation of alveolar macrophages plays an important role in the pathogenesis of silicosis. The deposition of fine silica particles in alveoli and the ingestion of silica particles by alveolar macrophages trigger pro-inflammatory and pro-fibrotic responses. However, molecular mechanisms of the dysregulated alveolar macrophage responses remain elusive. Using a mouse model of silicosis, our preliminary studies indicate that myeloid HDAC6 plays an essential role in the pathogenesis of silicosis. In the proposed studies, we will test the hypothesis that myeloid HDAC6 is a key mediator of pro-inflammatory and pro-fibrotic responses in silicosis. We will investigate the specific role of myeloid HDAC6 in silicosis and evaluate the therapeutic potential of HDAC6 as a target to treat silicosis.