Regulation of alveolar epithelial homeostasis in acute lung injury

急性肺损伤中肺泡上皮稳态的调节

• 批准号: 8459947
• 负责人: Jieru Wang
• 金额: $ 37.72万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459947
• 关键词: AIM2 gene; Acute Lung Injury; Allergic Disease; Alveolar; Alveolar Macrophages; Animal Model; Asthma; Bacteria; Cell Communication; Cell Culture System; Cells; Cessation of life; Child; DNA Virus Infections; Data; Diffuse; Disease; Distal; Economics; Epithelial; Epithelial Cells; Gases; Goals; Homeostasis; Hospitalization; Host Defense; Human; Immune response; Impairment; In Vitro; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Interleukins; Laboratories; Lower respiratory tract structure; Lung; Manuscripts; Measures; Mediating; Molecular; Mus; Pathogenicity; Patients; Play; Primary Cell Cultures; Production; Public Health; Pulmonary Edema; RNA; RNA Virus Infections; Regulation; Role; Small Interfering RNA; System; Therapeutic Agents; Tight Junctions; Tissues; Type II Epithelial Receptor Cell; Viral; Virus; Virus Activation; Virus Diseases; cell type; cytokine; improved; in vivo; in vivo Model; influenzavirus; injury and repair; macrophage; mortality; mouse model; novel; novel therapeutics; pandemic disease; pandemic influenza; repaired; seasonal influenza; transmission process; treatment strategy; young adult

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.

描述（由申请人提供）：该项目旨在确定在 2009 年 H1N1 大流行性流感病毒引起的急性肺损伤中如何调节人肺上皮稳态。由于 H1N1 大流行病毒的快速传播和致病性增加的可能性很大，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，比季节性流感病毒引起更严重的疾病，包括弥漫性肺泡损伤和肺水肿。为了确定这种组织损伤的机制，研究被病毒感染的特定细胞非常重要。因此，我们的研究将集中于人肺肺泡区域的细胞。我们的 该方法的新颖之处在于，我们将研究 2009 H1N1 大流行病毒对从同一健康肺供体分离的人肺泡上皮细胞和肺泡巨噬细胞的原代培养物的影响。我们使用该系统获得的初步数据表明 AIM2 炎性体和细胞因子 TSLP 均参与宿主对流感病毒感染的反应。 AIM2 炎性体对于宿主防御细菌和 DNA 病毒感染很重要，但其在 RNA 病毒感染中的作用此前尚未确定。在这里，我们将确定 AIM2 炎症小体在原代人 ATII 细胞和 H1N1 流感诱导的上皮损伤期间小鼠模型中的功能和机制。我们假设 AIM2 是流感病毒在肺泡上皮细胞中诱导的主要炎症小体。 AIM2缺陷的细胞和AIM2缺陷的小鼠在流感感染期间会出现更多的上皮屏障损伤。 TSLP 在哮喘等过敏性疾病中发挥着关键作用，但其对上皮屏障的影响尚未明确。我们将使用体外和体内模型确定 TSLP 在流感感染期间保护肺泡上皮屏障的作用。我们假设炎症小体激活将增强肺泡上皮细胞 TSLP 的产生。流感刺激的 TSLP 将通过增强细胞之间的紧密连接和/或刺激上皮细胞来改善流感在体外和体内受损的屏障 增殖。此外，肺泡上皮细胞与巨噬细胞之间的细胞间相互作用将增强上皮细胞释放TSLP。我们的研究将揭示流感急性肺损伤期间肺泡上皮屏障调节的新机制，从而揭示降低流感引起的死亡率的潜在新治疗策略。