Inflammasomes in Hyperoxic Acute Lung Injury

高氧急性肺损伤中的炎症小体

基本信息

批准号：
8789379
负责人：
Narasaiah Kolliputi
金额：
$ 36.2万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8789379
关键词：
Acute Lung Injury Acute monocytic leukemia Alveolar Alveolar Macrophages Apoptosis Attenuated CISH gene Cardiovascular Diseases Cell Death Cell Line Cell physiology Cells Cessation of life Clinical Coculture Techniques Complex Data Development Disease Epithelial Epithelial Cells Event Exposure to Goals Green Fluorescent Proteins Health Human Hyperoxia Incidence Inflammation Inflammatory Injury Lead Leucine-Rich Repeat Life Lung Lung diseases MAP3K5 gene Mediating Modeling Mus Oxidants Patients Permeability Pharmaceutical Preparations Processed Genes Proteins Reactive Oxygen Species Resistance Resolution Role Signal Transduction Small Interfering RNA Syndrome Testing Therapeutic Therapeutic Agents Therapeutic Intervention Type II Epithelial Receptor Cell Ubiquitination United States Virus Wild Type Mouse Work alveolar type II cell base cytokine in vivo insight lung injury monolayer mortality novel novel therapeutics overexpression protective effect receptor research study response

项目摘要

DESCRIPTION (provided by applicant): The work, as detailed in this proposal, has focused on the mechanism(s) of protection that Suppressor of Cytokine Signaling - 1 (SOCS-1) confers in the setting of hyperoxic acute lung injury (HALI). Our preliminary data demonstrated that adenoviral treated mice that overexpress the suppressor of cytokine signaling-1(Ad-SOCS-1) are remarkably resistant to hyperoxic acute lung injury (HALI) and live significantly longer in hyperoxia when compared to green fluorescent protein tagged adeno virus (Ad-GFP) treated mice. SOCS-1 overexpressing mice are protected from hyperoxia-induced inflammation, which is associated with inactivation of purinergic P2X7 receptor (P2X7R)-mediated inflammasome, thus demonstrating a critical role for SOCS-1 in inflammasome-mediated inflammation. Either inflammasome silencing or SOCS-1 overexpression in monocytic cell line (THP-1) and co-cultured with alveolar type II (ATII) monolayer abolishes hyperoxia induced transepithelial permeability across mouse ATII cell monolayers and abrogates hyperoxia-induced secretion of pro-inflammatory cytokines. SOCS-1 overexpressing mice are protected from hyperoxia-induced inflammation and apoptosis, which is associated with apoptosis signal-regulating kinase 1 (ASK-1) inhibition. SOCS-1- induced protection against oxidant-induced death-inducing signaling complex (DISC) mediated apoptosis is associated with ASK-1 ubiquitination and degradation. These studies lead us to hypothesize that SOCS-1 confers protection against HALI by inhibiting inflammasome-mediated inflammation and DISC-induced apoptosis via ASK-1 degradation. We propose the following specific aims to investigate our hypothesis: Aim 1: To identify the role of ASK-1 in SOCS-1-induced protection against hyperoxia-induced DISC and inflammasome formation. Aim 2: To determine whether activation of ASK-1 has a role in hyperoxia-induced P2X7R mediated inflammasome formation. Aim 3: To identify the role of inflammasome in SOCS-1-induced protection against hyperoxia-induced inflammation and epithelial permeability. The proposed studies will elucidate the mechanisms by which SOCS-1 protects against HALI and will identify the cellular processes and genes critical for protection of the lung. The proposed studies will elucidate the precise role of SOCS-1 mediated inflammasome in acute lung injury (ALI) could also lead to the discovery of a totally novel therapeutic class of drugs that suppresses inflammation in ALI.

描述（由申请人提供）：如本提案中详述的，该工作重点关注细胞因子信号传导抑制因子 - 1 (SOCS-1) 在高氧性急性肺损伤 (HALI) 中所赋予的保护机制。我们的初步数据表明，与绿色荧光蛋白标记的腺病毒相比，经过腺病毒治疗的过度表达细胞因子信号传导抑制因子-1（Ad-SOCS-1）的小鼠对高氧急性肺损伤（HALI）具有显着的抵抗力，并且在高氧状态下的寿命显着更长(Ad-GFP) 处理的小鼠。 SOCS-1 过表达小鼠免受高氧诱导的炎症的影响，这与嘌呤能 P2X7 受体 (P2X7R) 介导的炎症小体的失活有关，从而证明了 SOCS-1 在炎症小体介导的炎症中的关键作用。单核细胞系 (THP-1) 中炎症小体沉默或 SOCS-1 过表达以及与 II 型肺泡 (ATII) 单层细胞共培养可消除高氧诱导的跨小鼠 ATII 细胞单层的跨上皮通透性，并消除高氧诱导的促炎细胞因子的分泌。 SOCS-1 过表达小鼠可免受高氧诱导的炎症和细胞凋亡的影响，这与细胞凋亡信号调节激酶 1 (ASK-1) 抑制有关。 SOCS-1 诱导的针对氧化剂诱导死亡诱导信号复合物 (DISC) 介导的细胞凋亡的保护与 ASK-1 泛素化和降解相关。这些研究使我们推测 SOCS-1 通过抑制炎性体介导的炎症和通过 ASK-1 降解抑制 DISC 诱导的细胞凋亡来提供针对 HALI 的保护。我们提出以下具体目标来研究我们的假设：目标 1：确定 ASK-1 在 SOCS-1 诱导的针对高氧诱导的 DISC 和炎症小体形成的保护中的作用。目标 2：确定 ASK-1 的激活是否在高氧诱导的 P2X7R 介导的炎症小体形成中发挥作用。目标 3：确定炎症小体在 SOCS-1 诱导的针对高氧诱导的炎症和上皮通透性的保护中的作用。拟议的研究将阐明 SOCS-1 预防 HALI 的机制，并将确定对保护肺部至关重要的细胞过程和基因。拟议的研究将阐明 SOCS-1 介导的炎症小体在急性肺损伤 (ALI) 中的确切作用，也可能导致发现一类全新的治疗药物，用于抑制 ALI 炎症。