Gene transfer of MRCKα rescues lipopolysaccharide-induced acute lung injury by restoring alveolar capillary barrier function.
Gene transfer of MRCKα rescues lipopolysaccharide-induced acute lung injury by restoring alveolar capillary barrier function.
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DOI：
10.1038/s41598-021-99897-3
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发表时间：
2021-10-21
影响因子：
4.6
通讯作者：
Dean DA
中科院分区：
文献类型：
--
作者：
Liu J;Dean DA
急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)的特征是肺泡水肿堆积，肺泡液体清除(AFC)减少，肺泡-毛细血管屏障破坏，以及大量炎症，所有这些都导致急性呼吸衰竭。长期以来，提高AFC一直被认为是ARDS基因治疗的主要治疗目标之一。我们先前的研究表明，电穿孔介导的Na+，K+-ATPaseβ1亚单位的基因传递不仅增加了AFC，而且通过上调紧密连接蛋白来恢复肺泡屏障功能，从而治疗内毒素诱导的小鼠ALI。我们确定MRCKα是β1的相互作用伙伴，它介导了培养的肺泡上皮细胞的这种上调。在这项研究中，我们研究了电穿孔介导的MRCKα基因转移到肺内是否可以减轻体内内毒素诱导的急性肺损伤。与接受非表达质粒的小鼠相比，接受mRCKα质粒的小鼠表现出减轻了内毒素增加的肺水肿和肺渗漏，恢复了紧密连接蛋白的表达，并改善了总体结果。有趣的是，mRCKα的基因转移并没有改变AFC的比率。使用培养的微血管内皮细胞和小鼠的研究表明，β1和MRCKα上调了肺泡上皮细胞和毛细血管内皮细胞的连接复合体，我们的方法可能会对其中一个或两个屏障产生积极影响。我们的数据支持ALI/ARDS的治疗模型，在该模型中，仅改善肺泡-毛细血管屏障功能可能比改善肺泡液清除更有益。
Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is characterized by alveolar edema accumulation with reduced alveolar fluid clearance (AFC), alveolar-capillary barrier disruption, and substantial inflammation, all leading to acute respiratory failure. Enhancing AFC has long been considered one of the primary therapeutic goals in gene therapy treatments for ARDS. We previously showed that electroporation-mediated gene delivery of the Na+, K+-ATPase β1 subunit not only increased AFC, but also restored alveolar barrier function through upregulation of tight junction proteins, leading to treatment of LPS-induced ALI in mice. We identified MRCKα as an interaction partner of β1 which mediates this upregulation in cultured alveolar epithelial cells. In this study, we investigate whether electroporation-mediated gene transfer of MRCKα to the lungs can attenuate LPS-induced acute lung injury in vivo. Compared to mice that received a non-expressing plasmid, those receiving the MRCKα plasmid showed attenuated LPS-increased pulmonary edema and lung leakage, restored tight junction protein expression, and improved overall outcomes. Interestingly, gene transfer of MRCKα did not alter AFC rates. Studies using both cultured microvascular endothelial cells and mice suggest that β1 and MRCKα upregulate junctional complexes in both alveolar epithelial and capillary endothelial cells, and that one or both barriers may be positively affected by our approach. Our data support a model of treatment for ALI/ARDS in which improvement of alveolar-capillary barrier function alone may be of more benefit than improvement of alveolar fluid clearance.
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影响因子：
5.1
作者：
Lin, X.;Barravecchia, M.;Dean, D. A.
通讯作者：
Dean, D. A.
影响因子：
3.1
作者：
Emr, Bryanna M.;Roy, Shreyas;Dean, David A.
通讯作者：
Dean, David A.
影响因子：
16.6
作者：
Mammoto, Akiko;Mammoto, Tadanori;Ingber, Donald E.
通讯作者：
Ingber, Donald E.
影响因子：
20.1
作者：
Dumasius, V;Sznajder, JI;Factor, P
通讯作者：
Factor, P
影响因子：
3.3
作者：
GORIN, AB;STEWART, PA
通讯作者：
STEWART, PA