Regulation of alveolar epithelial homeostasis in acute lung injury

描述（由申请人提供）：本项目旨在确定2009年H1N1大流行性流感病毒引起的急性肺损伤如何调节人肺上皮稳态。由于甲型H1N1流感大流行病毒的传播速度快，致病性极有可能增加，因此迫切需要了解宿主对病毒感染的反应。这种病毒以远端肺细胞为目标，并导致比季节性流感病毒更严重的疾病，包括弥漫性肺泡损伤和肺水肿。为了明确这种组织损伤的机制，研究被病毒感染的特定细胞是很重要的。因此，我们的研究将集中在人肺肺泡区的细胞上。我们的

DESCRIPTION (provided by applicant): This project aims to determine how human lung epithelial homeostasis is regulated in acute lung injury induced by the 2009 H1N1 pandemic influenza virus. Because of the rapid transmission and high potential for increased pathogenicity of the H1N1 pandemic virus, there is an urgent need to understand the host response against viral infection. This virus targets distal lung cells and causes more severe disease than seasonal influenza virus, including diffuse alveolar damage and pulmonary edema. To define the mechanism of this tissue injury, it is important to study the specific cells that are infected by te virus. Therefore, our studies will focus on the cells in the alveolar region of the human lung. Our approach is novel in that we will study the effect of 2009 H1N1 pandemic virus on primary cultures of human alveolar epithelial cells and alveolar macrophages isolated from the same healthy lung donors. We have preliminary data using this system that suggests the involvement of both the AIM2 inflammasome and the cytokine TSLP in host response to influenza virus infection. The AIM2 inflammasome is important for host defense against bacteria and DNA virus infection, but a role for it in RNA virus infection has not previously been identified. Here we wil determine the function and mechanism of the AIM2 inflammasome in primary human ATII cells and in a mouse model during H1N1 influenza-induced epithelial injury. We hypothesize that AIM2 is the primary inflammasome induced by influenza virus in alveolar epithelial cells. AIM2 deficient cells and AIM2 deficient mice will have more impairment of the epithelial barrier during influenza infection. TSLP plays a key role in allergic diseases such as asthma, but its effect on the epithelial barrier is not yet defined. We will determine the role of TSLP in protecting the alveolar epithelial barrier during influenza infection using both in vitro and in vivo models. We hypothesize that inflammasome activation will enhance the TSLP production by alveolar epithelial cells. Influenza-stimulated TSLP will improve the damaged barrier by influenza both in vitro and in vivo through enhancing the tight junctions between cells and/or stimulating epithelial proliferation. In addition, the cell-cell interaction between alveolar epithelial cells and macrophages will enhance the release of TSLP by epithelial cells. Our study will reveal novel mechanisms for the regulation of the alveolar epithelial barrier during acute lung injury by influenza, thereby uncovering potential novel therapeutic strategies for reducing influenza-induced mortality.