Caveolin-1-mediated senescence, chronic inflammation and age-related lung disease

描述（由申请人提供）：肺气肿是一种与年龄相关的慢性炎症性疾病，主要与暴露于香烟烟雾有关，由肺部蛋白酶/抗蛋白酶失衡引起。确定炎症介质的细胞起源及其表达和功能的机制对于深入了解慢性炎症和年龄相关性肺部疾病之间的联系至关重要。衰老细胞的特征是不可逆的细胞周期停滞。它们在体外保持代谢活性，并能够分泌炎症介质。长期暴露于香烟烟雾可诱导成纤维细胞衰老，在肺气肿患者的肺成纤维细胞中可发现衰老的特征。有趣的是，我们发表的数据显示，caveolin-1促进小鼠慢性香烟烟雾诱导的肺成纤维细胞衰老。为了确定小洞蛋白-1介导的肺成纤维细胞衰老与肺气肿的发生之间是否存在因果关系，我们提出验证小洞蛋白-1介导的自噬抑制促进烟雾诱导的肺成纤维细胞自噬向衰老转变（AST）的新范式，AST成为促炎趋化因子的慢性来源，刺激炎症细胞释放蛋白酶。因此有助于肺气肿的发展。这一中心假设将通过追求三个特定目标来验证：目的1：确定肺成纤维细胞自噬向衰老转变的分子机制。假设：caveolin-1是一种新型的beclin-1相互作用蛋白。Caveolin-1通过破坏beclin-1/Vps34复合物抑制自噬，促进香烟诱导的肺成纤维细胞AST。目的2：明确香烟烟雾诱导的衰老成纤维细胞慢性释放炎症介质的分子机制和功能意义。假设：caveolin-1通过抑制eNOS活性，促进经AST的衰老成纤维细胞nf - kb介导的持续表达和分泌趋化因子，刺激炎症细胞释放蛋白酶。目的3：确定体内小泡蛋白-1介导的肺成纤维细胞衰老是否促进慢性肺炎症和肺气肿。假设：长期暴露于香烟烟雾诱导肺成纤维细胞衰老，从而促进慢性肺部炎症，并在体内以依赖于小泡蛋白1的方式参与肺气肿的发病机制。这些研究将确定小泡蛋白1介导的从自噬到衰老信号的转换是一个新的生物学过程，与慢性肺部炎症和肺气肿的发病机制有关。新的细胞和分子机制将被确定，这些机制有可能直接影响治疗与年龄有关的肺部疾病的新型治疗干预措施的未来发展。

DESCRIPTION (provided by applicant): Emphysema is an age-related and chronic inflammatory disease that is largely associated with exposure to cigarette smoke and caused by a protease/antiprotease imbalance in the lungs. The identification of the cellular origin of the inflammatory mediators and the mechanisms underlying their expression and function is fundamental for gaining insight into the link between chronic inflammation and age-related lung disease. Senescent cells are characterized by irreversible cell cycle arrest. They remain metabolically active and are capable of secreting mediators of inflammation in vitro. Chronic exposure to cigarette smoke induces senescence of fibroblasts and hallmarks of senescence are found in lung fibroblasts of emphysema patients. Interestingly, our published data show that caveolin-1 promotes chronic cigarette smoke-induced senescence of lung fibroblasts in mice. To determine whether a causal relationship exists between caveolin-1-mediated senescence of lung fibroblasts and development of emphysema, we propose to test the novel paradigm that caveolin-1-mediated inhibition of autophagy promotes smoke-induced autophagy-to-senescence transition (AST) of lung fibroblasts, which become a chronic source of pro-inflammatory chemokines that stimulate the release of proteases by inflammatory cells, therefore contributing to the development of pulmonary emphysema. This central hypothesis will be tested by pursuing three specific aims: Aim 1: Determine the molecular mechanism of autophagy-to-senescence transition in lung fibroblasts. Hypothesis: caveolin-1 is a novel beclin-1-interacting protein. Caveolin-1 promotes cigarette smoke-induced AST of lung fibroblasts by inhibiting autophagy through disruption of the beclin-1/Vps34 complex. Aim 2: Identify the molecular mechanism and functional significance of the cigarette smoke-induced and caveolin-1-mediated chronic release of mediators of inflammation by senescent fibroblasts. Hypothesis: caveolin-1, through inhibition of eNOS activity, promotes the NF-kB-mediated sustained expression and secretion of chemokines by senescent fibroblasts that underwent AST, which stimulate the release of proteases by inflammatory cells. Aim 3: Determine if caveolin-1-mediated senescence of lung fibroblasts promotes chronic lung inflammation and emphysema in vivo. Hypothesis: chronic exposure to cigarette smoke induces senescence of lung fibroblasts, which promote chronic lung inflammation and contribute to the pathogenesis of emphysema in a caveolin-1-dependent fashion in vivo. These investigations will identify the caveolin-1-mediated switch from autophagic to senescent signaling as a novel biological process that is relevant to chronic lung inflammation and the pathogenesis of emphysema. Novel cellular and molecular mechanisms will be determined that have the potential to directly impact the future development of novel therapeutic interventions for the treatment of age-related lung disease.