PDF(Pubmed)
Abstract：
Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease with no effective treatment that can reduce mortality or slow the disease progression. COPD is the third leading cause of global death and is characterized by airflow limitations due to chronic bronchitis and alveolar damage/emphysema. Chronic cigarette smoke (CS) exposure damages airway and alveolar epithelium and remains a major risk factor for the pathogenesis of COPD. We found that the expression of caveolin-1, a tumor suppressor protein; p53; and plasminogen activator inhibitor-1 (PAI-1), one of the downstream targets of p53, was markedly increased in airway epithelial cells (AECs) as well as in type II alveolar epithelial (AT2) cells from the lungs of patients with COPD or wild-type mice with CS-induced lung injury (CS-LI). Moreover, p53- and PAI-1-deficient mice resisted CS-LI. Furthermore, treatment of AECs, AT2 cells, or lung tissue slices from patients with COPD or mice with CS-LI with a seven amino acid caveolin-1 scaffolding domain peptide (CSP7) reduced mucus hypersecretion in AECs and improved AT2 cell viability. Notably, induction of PAI-1 expression via increased caveolin-1 and p53 contributed to mucous cell metaplasia and mucus hypersecretion in AECs, and reduced AT2 viability, due to increased senescence and apoptosis, which was abrogated by CSP7. In addition, treatment of wild-type mice having CS-LI with CSP7 by intraperitoneal injection or nebulization via airways attenuated mucus hypersecretion, alveolar injury, and significantly improved lung function. This study validates the potential therapeutic role of CSP7 for treating CS-LI and COPD. NEW & NOTEWORTHY Chronic cigarette smoke (CS) exposure remains a major risk factor for the pathogenesis of COPD, a debilitating disease with no effective treatment. Increased caveolin-1 mediated induction of p53 and downstream plasminogen activator inhibitor-1 (PAI-1) expression contributes to CS-induced airway mucus hypersecretion and alveolar wall damage. This is reversed by caveolin-1 scaffolding domain peptide (CSP7) in preclinical models, suggesting the therapeutic potential of CSP7 for treating CS-induced lung injury (CS-LI) and COPD.
摘要：
慢性阻塞性肺疾病（COPD）是一种使人衰弱的肺部疾病，没有有效的治疗方法可以降低死亡率或减缓疾病进展。COPD是全球死亡的第三大原因,其特征在于由慢性支气管炎和肺泡损伤/肺气肿引起的气流受限。慢性香烟烟雾暴露（CS）会损害气道和肺泡上皮，并且仍然是COPD发病的主要危险因素。我们发现caveolin-1，肿瘤抑制蛋白，p53和纤溶酶原激活物抑制剂-1（PAI-1）的表达，来自COPD患者或CS诱导的肺损伤(CS-LI)的野生型小鼠的气道上皮细胞(AECs)以及II型肺泡上皮细胞(AT2)中p53的下游靶标之一显著增加.此外，p53和PAI-1缺陷型小鼠抵抗CS-LI。此外，AECs的治疗,来自COPD患者的AT2细胞或肺组织切片，或具有具有七个氨基酸的caveolin-1支架结构域肽（CSP7）的CS-LI小鼠可减少AECs中的粘液分泌过多并改善AT2细胞活力。值得注意的是,通过增加的caveolin-1和p53诱导PAI-1表达有助于AECs中的粘液细胞化生和粘液分泌过多，并降低AT2的活力，由于衰老和凋亡增加，已被CSP7废除。此外,用CSP7通过腹膜内注射或通过气道雾化治疗具有CS-LI的野生型小鼠，肺泡损伤,显著改善肺功能。本研究验证了CSP7治疗CS-LI和COPD的潜在治疗作用。
