Inflammasomes in Hyperoxic Acute Lung Injury

高氧急性肺损伤中的炎症小体

• 批准号: 8213420
• 负责人: Narasaiah Kolliputi
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213420
• 关键词: Acute Lung Injury; Acute monocytic leukemia; Alveolar; Alveolar Macrophages; Apoptosis; Attenuated; Cardiovascular Diseases; Cell Death; Cell Line; Cell physiology; Cells; Cessation of life; Clinical; Coculture Techniques; Complex; Cytokine Inducible SH2-Containing Protein; Data; Development; Disease; Epithelial; Epithelial Cells; Event; Exposure to; Goals; Green Fluorescent Proteins; 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; Simulate; 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; public health relevance; receptor; research study; response

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. PUBLIC HEALTH RELEVANCE: Hyperoxia is a necessary part of treatment for patients with cardiovascular and pulmonary diseases. However, prolonged exposure to hyperoxia leads to acute lung injury (ALI). ALI is a major clinical problem in the United States with an estimated incidence rate of 262,500 patients and 40-50% mortality. Our preliminary data suggest that SOCS-1 protects against hyperoxia-induced inflammation and apoptosis. These protective effects of SOCS-1 in the setting of oxidative injury are associated with inflammasome inactivation. In this proposal we will study the role of inflammasome in acute lung injury. Our work may uncover new disease mechanisms and therapeutic approaches for lung injury associated syndromes.

描述（由申请人提供）：该提案中详细介绍的工作集中在细胞因子信号抑制器的保护机制上-1（SOCS -1）在过度氧化急性肺损伤（HALI）的情况下。我们的初步数据表明，与绿色荧光蛋白标记的腺病毒病毒（AD-GFP）治疗的MICE相比，腺病毒治疗的小鼠过表达细胞因子信号1（AD-SOCS-1）的抑制作用非常抵抗高氧化急性肺损伤（HALI），而在高氧中的寿命明显更长。 SOCS-1过表达的小鼠免受高氧诱导的炎症的保护，这与嘌呤能P2X7受体（P2X7R）介导的炎症体的失活有关，从而证明了SOCS-1在炎症体介导的炎症中的关键作用。单核细胞系（THP-1）中的炎性体沉默或SOCS-1过表达，并与肺泡II型（ATII）单层共同培养，废除了小鼠ATII细胞单层中的transepithelies诱导的transepithelial诱导的transepithelial渗透性，并消除了高氧诱导的促毒素的分泌症状毒素。 SOCS-1过表达的小鼠免受高氧诱导的炎症和凋亡的保护，这与凋亡信号调节激酶1（ASK-1）抑制有关。 SOCS-1诱导的保护对氧化剂诱导的诱导死亡的信号传导复合物（椎间盘）介导的凋亡与Ask-1泛素化和降解有关。这些研究使我们假设SOCS-1通过抑制炎症介导的炎症和椎间盘诱导的凋亡通过Ask-1降解来赋予对HALI的保护。我们提出以下具体目的来研究我们的假设：目标1：确定Ask-1在SOCS-1诱导的针对高氧诱导的椎间盘和炎症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介导的炎性体形成中起作用。 AIM 3：确定炎症体在SOCS-1诱导的针对高氧诱导的炎症和上皮渗透性中的作用。拟议的研究将阐明SOCS-1预防HALI的机制，并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介导的炎症体在急性肺损伤（ALI）中的精确作用，还可能导致发现完全新颖的治疗类药物，这些药物抑制了ALI中的炎症。 公共卫生相关性：高氧是心血管和肺部疾病患者治疗的必要部分。然而，长时间暴露于高氧导致急性肺损伤（ALI）。在美国，阿里是一个主要的临床问题，估计发病率为262,500例，死亡率为40-50％。我们的初步数据表明，SOCS-1可以预防高氧引起的炎症和凋亡。 SOCS-1在氧化损伤环境中的这些保护作用与炎性体灭活有关。在此提案中，我们将研究炎性体在急性肺损伤中的作用。我们的工作可能会发现有关肺损伤综合症的新疾病机制和治疗方法。