Cigarette smoke influences alveolar type II cell-derived exosomes

摘要 肺泡II型(ATII)细胞产生和分泌肺表面活性物质。它们具有干细胞潜能， 损伤后的上皮细胞增殖和修复。肺气肿的特点是肺泡壁破坏。它 是由吸烟和二手烟引起的。这种暴露导致的高氧化应激导致 对ATII细胞损伤、线粒体和核DNA损伤。DNA双链断裂(DSB)是最常见的 对基因组和线粒体DNA的严重威胁。线粒体DNA(MtDNA)更易感染 对氧化损伤的影响比核DNA大，这是因为缺乏组蛋白来起到防止损伤的作用 这些因素以及有限的DNA修复能力。未能修复mtDNA双链断裂可触发形成 突变、缺失和有丝分裂。此外，受损的mtdna可以从线粒体分泌到 胞质和胞外间隙通过外体。Exosome是一种小的膜小泡， 在正常或病理条件下从细胞中释放出来。它们也可以作为信号载体，通过 将蛋白质、DNA和RNA运送到受体细胞，导致其基因改变 表达、增殖和分化。此外，据报道，CD147调节 线粒体复合体I活性与线粒体蛋白相互作用引起的细胞凋亡。CD147是 一种细胞外基质金属蛋白酶(MMPs)的诱导剂，已知能刺激MMPs的表达。我们 检测到ATII细胞来源的外体中存在高水平的线粒体DNA和CD147 肺气肿。我们将使用抗CD147的单抗来阻断其有害功能。我们的假设是 TinhaetxmotsDoNmAesansdecCrDet1e4d7由ATII细胞在肺气肿中诱导受体细胞损伤。单抗 抗CD147会阻止含有有害内容的外切体的循环。在具体目标#1中，我们将确定 肺气肿患者ATII细胞来源外切体的功能。我们将研究Exosomal的作用 受体ATII细胞上的线粒体DNA和CD147。在特定的目标#2中，我们将确定单抗 封闭CD147可降低外切体对受体培养的ATII细胞的损伤作用。vt.在.的基础上 完成这项拟议的研究后，我们将表征ATII细胞分泌的外切体在 肺气肿及其对受体细胞的影响。抗胞外体CD147的单抗可以提供一种 针对这种疾病进展的新的治疗策略。

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.