Abstract
理由Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2-receptor 1 (PLA2R1) as a positive regulator of cell senescence acting通过jak/stat信号。然而,它在病理学中的作用仍然未知。在这里,我们评估了PLA2R1诱导的COPD和肺肺气肿发病机理中的衰老。
Methods评估COPD患者肺和培养的肺细胞中细胞衰老的评估,并受到PLA2R1敲低的对照PLA2R1JAK1/2抑制剂鲁辛尼的基因转导和治疗。评估是否PLA2R1upregulation caused lung lesions, we developed transgenic mice overexpressingPLA2R1((PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying thePLA2R1基因(LV-PLA2R1mice).
测量和结果We found thatPLA2R1was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs.PLA2R1敲低扩大了这些细胞的人口加倍能力,并抑制了它们促炎性衰老相关的分泌表型(SASP)。PLA2R1介导的COPD中的细胞衰老在很大程度上通过用有效的JAK1/2抑制剂鲁辛替尼治疗来逆转。5个月大PLA2R1-TG mice exhibited lung-cell senescence and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV-PLA2R1经过处理的小鼠在4周内形成了肺部肺气肿,这显着通过违反治疗来减弱。
ConclusionOur data support a major role for PLA2R1 activation in driving lung-cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.
Footnotes
This manuscript has recently been accepted for publication in theEuropean Respiratory Journal。它在我们的生产团队复制和排版之前以其公认的形式出版。在完成这些生产过程并批准了由此产生的证明之后,该文章将转移到最新一期ERJonline. Please open or download the PDF to view this article.
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- Received2020年3月18日。
- 公认2020年12月28日。
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