Inflammatory Injury Caused by Silica Exposure

项目摘要 在美国，超过200万人在工作中暴露于可吸入的结晶二氧化硅。吸入 含有可吸入结晶二氧化硅的粉尘引起矽肺，其特征是慢性 炎症和肺纤维化。接触二氧化硅也会增加显影的风险 自身免疫性疾病和癌症。矽肺患者的中位生存期为6年， 诊断.矽肺的病理生理机制尚未完全了解。目前尚无 有效治疗这种毁灭性疾病。据报道，失调 肺泡巨噬细胞的活化在矽肺发病中起重要作用。沉积 肺泡中细小二氧化硅颗粒的减少和肺泡巨噬细胞对二氧化硅颗粒的摄取触发了 促炎和促纤维化反应。然而， 失调的肺泡巨噬细胞反应仍然难以捉摸。使用小鼠硅肺模型， 我们的初步研究表明，髓样HDAC6在发病机制中起重要作用， 硅肺在拟议的研究中，我们将测试髓样HDAC6是一个关键的假设， 矽肺中促炎和促纤维化反应的介质。我们将调查 骨髓HDAC6在矽肺中的特异性作用，并评估HDAC6作为一种治疗药物的治疗潜力。 以治疗矽肺为目标。

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.