Akt activation sustains silica induced inflammation

描述(申请人提供)：矽肺是一种职业性肺部疾病，因吸入二氧化硅微粒而导致慢性炎症和进行性肺纤维化。肺泡巨噬细胞(AM)吞噬吸入的二氧化硅颗粒并随后激活AM是矽肺发病机制中的关键步骤；然而，特定的细胞内信号通路参与调节这一过程的机制在很大程度上仍然未知。这项研究的目的是验证这一中心假设，即二氧化硅诱导的肿瘤坏死因子α的产生通过激活AM中的Akt信号通路来维持炎症本研究的具体目的是：1)评估暴露于SiO_2后AM的细胞命运，2)确定SiO_2对AM中Akt信号通路的影响，以及3)阐明SiO_2诱导的肿瘤坏死因子α产生刺激Akt信号通路和改变呼叫命运(细胞凋亡与存活)的能力。明确这一信号通路在调节AM激活和细胞命运中的作用是很有意义的，因为更好地了解所涉及的分子事件可能使关键的生化通路成为更有效地诊断和治疗职业性肺部疾病的靶点。

DESCRIPTION (provided by applicant): Silicosis is an occupational lung disease resulting from the inhalation of silica particles which causes chronic inflammation and progressive pulmonary fibrosis. Phagocytosis of inhaled silica particles by alveolar macrophages (AM) and subsequent activation of AM is a crucial step in the pathogenesis of silicosis; however, the participation of specific intracellular signaling pathways in regulating this process remains largely unknown. The goal of this study is to test the central hypothesis that silica induced production of TNF alpha sustains inflammation by activating the Akt signaling pathway in AM. The specific aims of this proposed research are: 1) to assess the cellular fate of AM following exposure to silica, 2) to determine the effects of silica on the Akt signaling pathways in AM, and 3) to elucidate the ability of silica induced TNF alpha production to stimulate the Akt signaling pathway and alter call fate (apoptosis vs. survival). Defining the function of this signaling pathway in regulating AM activation and cell fate is of interest because a better understanding of the molecular events involved may permit targeting of key biochemical pathways for more effective diagnosis and treatment of occupational lung diseases.