The role of Src & ERK1/2 kinases in inspiratory resistive breathing induced acute lung injury and inflammation.
The role of Src & ERK1/2 kinases in inspiratory resistive breathing induced acute lung injury and inflammation.
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DOI：
10.1186/s12931-017-0694-7
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发表时间：
2017-12-13
影响因子：
5.8
通讯作者：
Vassilakopoulos T
中科院分区：
文献类型：
--
作者：
Toumpanakis D;Vassilakopoulou V;Sigala I;Zacharatos P;Vraila I;Karavana V;Theocharis S;Vassilakopoulos T
吸气阻力性呼吸（IRB）是阻塞性气道疾病的标志，由于吸气肌的剧烈收缩，其与大的负胸内压相关。IRB显示在先前健康的动物中诱导肺损伤。Src是一种多功能激酶，在肺中被机械应力激活。ERK 1/2激酶是Src的下游靶点。我们假设Src在IRB过程中在肺中被激活，介导ERK 1/2激活和IRB诱导的肺损伤。麻醉、气管造口术的成年大鼠通过双向非再呼吸阀自主呼吸。对吸气端口增加阻力，以提供最大值的50%的峰值潮气吸气压力（吸气阻力呼吸）。在IRB期间估计肺中Src和ERK 1/2的活化。IRB 6 h后，通过强迫振荡技术测量呼吸系统力学，并进行支气管肺泡灌洗（BAL）以测量总细胞计数和分类细胞计数以及总蛋白水平。检测肺组织标本中IL-1b和MIP-2a蛋白水平。测量湿肺重量与总体重之比，并估计伊文思蓝染料外渗以测量肺渗透性。通过组织学评价肺损伤。在IRB前30 min给予Src抑制剂PP-2或ERK 1/2活化抑制剂PD 98059。Src激酶在IRB开始后30分钟被激活。Src抑制可改善6 h IRB后BAL细胞数的增加，但不能改善肺中IL-1β和MIP-2a的增加。BAL总蛋白和肺损伤评分的增加不受影响。组织弹性的增加被部分抑制。Src抑制阻断ERK 1/2活化在3小时，但不是在6小时的IRB。ERK 1/2抑制可改善IRB 6 h后BAL细胞构成的增加，阻断IL-1β的增加，并使伊文思蓝外渗和肺湿重恢复至对照值。BAL总蛋白和弹性的增加受到部分影响。与6 h IRB相比，ERK 1/2抑制未显著改变总肺损伤评分。Src和ERK 1/2在IRB后肺中被激活并参与IRB诱导的肺损伤。
Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with large negative intrathoracic pressures, due to strenuous contractions of the inspiratory muscles. IRB is shown to induce lung injury in previously healthy animals. Src is a multifunctional kinase that is activated in the lung by mechanical stress. ERK1/2 kinase is a downstream target of Src. We hypothesized that Src is activated in the lung during IRB, mediates ERK1/2 activation and IRB-induced lung injury. Anaesthetized, tracheostomized adult rats breathed spontaneously through a 2-way non-rebreathing valve. Resistance was added to the inspiratory port to provide a peak tidal inspiratory pressure of 50% of maximum (inspiratory resistive breathing). Activation of Src and ERK1/2 in the lung was estimated during IRB. Following 6 h of IRB, respiratory system mechanics were measured by the forced oscillation technique and bronchoalveolar lavage (BAL) was performed to measure total and differential cell count and total protein levels. IL-1b and MIP-2a protein levels were measured in lung tissue samples. Wet lung weight to total body weight was measured and Evans blue dye extravasation was estimated to measure lung permeability. Lung injury was evaluated by histology. The Src inhibitor, PP-2 or the inhibitor of ERK1/2 activation, PD98059 was administrated 30 min prior to IRB. Src kinase was activated 30 min after the initiation of IRB. Src inhibition ameliorated the increase in BAL cellularity after 6 h IRB, but not the increase of IL-1β and MIP-2a in the lung. The increase in BAL total protein and lung injury score were not affected. The increase in tissue elasticity was partly inhibited. Src inhibition blocked ERK1/2 activation at 3 but not at 6 h of IRB. ERK1/2 inhibition ameliorated the increase in BAL cellularity after 6 h of IRB, blocked the increase of IL-1β and returned Evans blue extravasation and wet lung weight to control values. BAL total protein and the increase in elasticity were partially affected. ERK1/2 inhibition did not significantly change total lung injury score compared to 6 h IRB. Src and ERK1/2 are activated in the lung following IRB and participate in IRB-induced lung injury.
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影响因子：
4.8
作者：
Han, B;Bai, XH;Liu, MY
通讯作者：
Liu, MY
影响因子：
4.3
作者：
Jarenbäck L;Ankerst J;Bjermer L;Tufvesson E
通讯作者：
Tufvesson E
影响因子：
24.3
作者：
Lederer, D. J.;Jelic, S.;Bhattacharya, J.
通讯作者：
Bhattacharya, J.
高氧通过促丝分裂原激活的蛋白激酶增加了呼吸机诱导的肺损伤：一种前瞻性，受控的动物实验。
DOI：
10.1186/cc5704
发表时间：
2007
期刊：
Critical care (London, England)
影响因子：
--
作者：
Li LF;Liao SK;Ko YS;Lee CH;Quinn DA
通讯作者：
Quinn DA
DOI：
10.1161/atvbaha.110.222208
发表时间：
2011-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Liu G;Vogel SM;Gao X;Javaid K;Hu G;Danilov SM;Malik AB;Minshall RD
通讯作者：
Minshall RD