Critical role for the lung endothelial nonmuscle myosin light-chain kinase isoform in the severity of inflammatory murine lung injury.
Critical role for the lung endothelial nonmuscle myosin light-chain kinase isoform in the severity of inflammatory murine lung injury.
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DOI：
10.1002/pul2.12061
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发表时间：
2022-04
影响因子：
2.6
通讯作者：
Garcia, Joe G. N.
中科院分区：
文献类型：
--
作者：
Kempf, Carrie L.;Sammani, Saad;Bermudez, Tadeo;Song, Jin H.;Hernon, Vivian Reyes;Hufford, Matthew K.;Burt, Jessica;Camp, Sara M.;Dudek, Steven M.;Garcia, Joe G. N.
肌球蛋白轻链激酶（nmMLCK）的非肌肉亚型（细胞骨架机制的主要细胞调节因子）的整体敲除在炎症性肺损伤的临床前小鼠模型中具有强保护作用。本研究旨在评估内皮细胞（EC）nmMLCK对脂多糖（LPS）和机械通气呼吸机诱导的肺损伤或通气（VILI）引起的小鼠炎性肺损伤严重程度的特异性贡献。在以下小鼠中评估了对LPS/VILI联合暴露的反应：（i）野生型（WT）C57 BL/6 J小鼠;（ii）nmMLCK整体缺失的转基因小鼠（nmMylk −/−）;（iii）nmMLCK过表达限于内皮的转基因nmMylk −/−小鼠（nmMylk −/−/ec-tg+）。肺部炎症指标包括肺组织学、支气管肺泡灌洗（BAL）多形核白细胞（PMN）、肺蛋白生化、组织白蛋白水平、伊文思蓝染料（EBD）肺外渗和血浆细胞因子（白细胞介素-6 [IL-6]、角质形成细胞趋化因子[KC]/IL-8、IL-1bβ、细胞外烟酰胺磷酸核糖基转移酶、肿瘤坏死因子-α）。与WT C57 BL/6 J小鼠相比，在nmMLCK整体缺失的小鼠中，LPS/VILI诱导的肺损伤的严重程度显著降低，这反映在肺匀浆中的组织学炎性肺损伤、BAL PMN计数、有丝分裂原活化蛋白激酶和NF-kB通路活化、血浆细胞因子水平和肺通透性参数（BAL蛋白、组织白蛋白水平升高、EBD肺外渗）降低。相反，与WT小鼠相比，EC中nmMLCK限制性过表达的小鼠（nmMylk −/−/ec-tg+）显示LPS/VILI诱导的肺损伤严重程度显著持续。总之，这些研究强烈支持EC nmMLCK在驱动临床前炎性肺损伤严重程度中的作用。EC nmMLCK的精确靶向可能代表减少肺部炎症以及肺和全身血管通透性的有吸引力的治疗策略。
Global knockout of the nonmuscle isoform of myosin light‐chain kinase (nmMLCK), a primary cellular regulator of cytoskeletal machinery, is strongly protective in preclinical murine models of inflammatory lung injury. The current study was designed to assess the specific contribution of endothelial cell (EC) nmMLCK to the severity of murine inflammatory lung injury produced by lipopolysaccharide (LPS) and mechanical ventilation ventilator‐induced lung injury or ventilation (VILI). Responses to combined LPS/VILI exposure were assessed in: (i) wild‐type (WT) C57BL/6J mice; (ii) transgenic mice with global deletion of nmMLCK (nmMylk −/−); (iii) transgenic nmMylk −/− mice with overexpression of nmMLCK restricted to the endothelium (nmMylk −/−/ec‐tg+). Lung inflammation indices included lung histology, bronchoalveolar lavage (BAL) polymorphonuclear leukocytes (PMNs), lung protein biochemistry, tissue albumin levels, Evans blue dye (EBD) lung extravasation, and plasma cytokines (interleukin‐6 [IL‐6], keratinocyte chemoattractant [KC]/IL‐8, IL‐1bβ, extracellular nicotinamide phosphoribosyltransferase, tumor necrosis factor‐α). Compared to WT C57BL/6J mice, the severity of LPS/VILI‐induced lung injury was markedly reduced in mice with global nmMLCK deletion reflected by reductions in histologic inflammatory lung injury, BAL PMN counts, mitogen‐activated protein kinase, and NF‐kB pathway activation in lung homogenates, plasma cytokine levels, and parameters of lung permeability (increased BAL protein, tissue albumin levels, EBD lung extravasation). In contrast, mice with restricted overexpression of nmMLCK in EC (nmMylk −/−/ec‐tg+) showed significant persistence of LPS/VILI‐induced lung injury severity compared to WT mice. In conclusion, these studies strongly endorse the role of EC nmMLCK in driving the severity of preclinical inflammatory lung injury. Precise targeting of EC nmMLCK may represent an attractive therapeutic strategy to reduce lung inflammation and both lung and systemic vascular permeability.
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影响因子：
3.7
作者：
Chen C;Wang P;Su Q;Wang S;Wang F
通讯作者：
Wang F
DOI：
10.1152/ajpgi.00412.2004
发表时间：
2005-03-01
影响因子：
4.5
作者：
Ma, TY;Boivin, MA;Said, HM
通讯作者：
Said, HM
影响因子：
2.6
作者：
Goldman, Julia L.;Sammani, Saad;Garcia, Joe G. N.
通讯作者：
Garcia, Joe G. N.
影响因子：
14.2
作者：
Gao, Li;Grant, Audrey V.;Barnes, Kathleen C.
通讯作者：
Barnes, Kathleen C.
DOI：
10.1165/rcmb.2005-0404oc
发表时间：
2006-04-01
影响因子：
6.4
作者：
Gao, L;Grant, A;Garcia, JGN
通讯作者：
Garcia, JGN