Cigarette smoke influences alveolar type II cell-derived exosomes

香烟烟雾影响肺泡 II 型细胞来源的外泌体

• 批准号: 9979287
• 负责人: Karim Bahmed
• 金额: $ 23.67万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979287
• 关键词: Address; Alveolar wall; Apoptosis; Applications Grants; Blocking Antibodies; Blood Circulation; Cell Death; Cell Separation; Cells; Characteristics; Clinical; Complex; Cytoplasm; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Development; Disease; Disease Progression; Epithelial; Epithelium; Extracellular Matrix; Extracellular Space; Failure; Functional disorder; Gene Expression; Genomic DNA; Goals; Histones; Human; In Vitro; Inflammatory; Injury; Lead; Location; Lung; Matrix Metalloproteinases; Membrane; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Monoclonal Antibodies; Mutation; Nuclear; Organ Donor; Oxidative Stress; Pathogenicity; Pathologic; Patients; Proliferating; Proteins; Pulmonary Emphysema; Pulmonary Surfactants; RNA; Reactive Oxygen Species; Reporting; Risk Factors; Role; Signal Transduction; Therapeutic; alveolar type II cell; cell injury; cigarette smoke; cigarette smoke-induced; cigarette smoking; effective therapy; environmental tobacco smoke; exosome; experience; mitochondrial dysfunction; novel therapeutic intervention; novel therapeutics; oxidative damage; repaired; stem cells; vesicular release

Abstract Alveolar type II (ATII) cells produce and secrete the pulmonary surfactant. They have stem cell potential, proliferate and restore the epithelium after damage. Emphysema is characterized by alveolar wall destruction. It is caused by cigarette smoking and second hand smoke. High oxidative stress induced by this exposure leads to ATII cell injury, mitochondrial and nuclear DNA damage. DNA double-strand breaks (DSBs) pose the most serious threat to the genomic and mitochondrial DNA. Mitochondrial DNA (mtDNA) is more susceptible to oxidative damage than nuclear DNA due to the lack of histones that serve as a barrier against damaging factors as well as limited DNA repair capacity. Failure to repair mtDNA DSBs can trigger a formation of mutations, deletions and mitophagy. Moreover, damaged mtDNA can be secreted from mitochondria to the cytoplasm and extracellular space via exosomes. Exosomes are small membrane vesicles that are released from the cell under normal or pathological conditions. They also serve as signaling vehicles by delivering proteins, DNA and RNA, to the recipient cells leading to alteration of their gene expression, proliferation, and differentiation. Furthermore, it has been reported that CD147 regulates complex I activity in mitochondria and cell apoptosis by interacting with mitochondrial proteins. CD147 is an extracellular matrix metalloproteinase (MMP) inducer and is known to stimulate MMPs expression. We detected high mtDNA and CD147 levels in ATII cell-derived exosomes obtained from patients with emphysema. We will use monoclonal antibody against CD147 to block its harmful function. Our hypothesis is tinhaetxmotsDoNmAesansdecCrDet1e4d7by ATII cells in emphysema induce injury in the recipient cells. Monoclonal antibody against CD147 will block circulation of exosomes with harmful content. In Specific Aim #1 we will determine the function of ATII cell-derived exosomes obtained from emphysema patients. We will study the role of exosomal mtDNA and CD147 on the recipient ATII cells. In Specific Aim #2, we will determine whether monoclonal antibody blocking CD147 will decrease the harmful function of exosomes on the recipient cultured ATII cells. Upon completion of the proposed study, we will have characterized the function of exosomes secreted by ATII cells in emphysema and their effect on the recipient cells. Monoclonal antibody against exosomal CD147 can provide a new therapeutic strategy against this disease progression.

摘要 肺泡II型（ATII）细胞产生并分泌肺表面活性物质。它们有干细胞潜能， 增殖并修复损伤后的上皮。肺气肿的特征是肺泡壁破坏。它 是由吸烟和二手烟引起的。这种暴露引起的高氧化应激导致 ATII细胞损伤，线粒体和核DNA损伤。DNA双链断裂（DSB）是 严重威胁到基因组和线粒体DNA。线粒体DNA（mtDNA）更易受影响 由于缺乏作为抗损伤屏障的组蛋白，比核DNA更容易受到氧化损伤 DNA修复能力有限。线粒体DNA双链断裂的修复失败会引发 突变、缺失和线粒体自噬。此外，受损的线粒体DNA可以从线粒体分泌， 细胞质和细胞外空间通过外来体。外来体是小的膜囊泡， 在正常或病理条件下从细胞中释放。它们也可以作为信号车辆， 将蛋白质、DNA和RNA递送到受体细胞，导致其基因改变 表达、增殖和分化。此外，据报道，CD147调节 复合物I通过与线粒体蛋白相互作用而在线粒体中的活性和细胞凋亡中起作用。CD147是 一种细胞外基质金属蛋白酶（MMP）诱导剂，并且已知刺激MMP表达。我们 检测到高mtDNA和CD147水平的ATII细胞来源的外来体获得自患者 肺气肿我们将用抗CD147的单克隆抗体阻断其有害功能。我们的假设是 肺气肿中ATII细胞诱导的DoNmAesansdecCrDet1e4d7损伤受体细胞。单克隆抗体 针对CD147的抗体将阻断含有有害成分的外泌体的循环。在具体目标#1中，我们将确定 从肺气肿患者获得的ATII细胞衍生的外泌体的功能。我们将研究外泌体的作用 线粒体DNA和CD147在受体ATII细胞上。在具体目标#2中，我们将确定单克隆抗体是否 阻断CD147将降低外来体对受体培养的ATII细胞的有害功能。后 完成所提出的研究后，我们将表征ATII细胞分泌的外泌体的功能， 肺气肿及其对受体细胞的影响。针对外泌体CD147的单克隆抗体可以提供 针对这种疾病进展的新治疗策略。