Akt activation sustains silica induced inflammation

描述（由申请人提供）：矽肺病是一种职业性肺病，由吸入二氧化硅颗粒引起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是矽肺发病的关键步骤；然而，特定的细胞内信号通路在调节这一过程中的参与仍然很大程度上是未知的。本研究的目的是验证核心假设，即二氧化硅通过激活AM中的Akt信号通路诱导TNF α的产生，从而维持炎症。本研究的具体目的是：1)评估暴露于二氧化硅后AM的细胞命运，2)确定二氧化硅对AM中Akt信号通路的影响，以及3)阐明二氧化硅诱导TNF α产生刺激Akt信号通路并改变细胞命运（凋亡与生存）的能力。确定这一信号通路在调节AM活化和细胞命运中的功能是有意义的，因为更好地了解所涉及的分子事件可能允许针对关键生化途径，从而更有效地诊断和治疗职业性肺病。

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.