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）：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。 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组成部分。然而，长时间暴露于高氧环境会导致急性肺损伤（ALI）。 ALI 是美国的一个主要临床问题，估计发病率为 262,500 名患者，死亡率为 40-50%。我们的初步数据表明 SOCS-1 可以防止高氧诱导的炎症和细胞凋亡。 SOCS-1 在氧化损伤中的这些保护作用与炎性体失活有关。在本提案中，我们将研究炎症小体在急性肺损伤中的作用。我们的工作可能会揭示肺损伤相关综合征的新疾病机制和治疗方法。