Haloperidol Attenuates Lung Endothelial Cell Permeability In Vitro and In Vivo.
Haloperidol Attenuates Lung Endothelial Cell Permeability In Vitro and In Vivo.
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DOI：
10.3390/cells10092186
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发表时间：
2021-08-25
期刊：
影响因子：
6
通讯作者：
Jacobson JR
中科院分区：
文献类型：
--
作者：
Colamonici MA;Epshtein Y;Chen W;Jacobson JR
我们以前报道过紧密连接蛋白claudin-5在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠模型中介导肺血管通透性。最近，据报道，氟哌啶醇，一种抗精神病药物，剂量依赖性地增加表达的claudin-5在体外和体内，在脑内皮细胞。值得注意的是，紧密连接蛋白-5在脑和肺组织中都高度表达。然而，氟哌啶醇对EC屏障功能的影响尚不清楚。我们假设氟哌啶醇增加肺EC claudin-5的表达并减弱激动剂诱导的肺EC屏障破坏。用不同浓度（0.1-10 μM）的氟哌啶醇预处理人肺动脉EC 24 h。对细胞裂解物进行蛋白质印迹，以检测claudin-5以及闭合蛋白和闭合蛋白-1（ZO-1）（两种其他紧密连接蛋白）。为了评估对屏障功能的影响，在用凝血酶（1 U/mL）处理前，用氟哌啶醇（10 µM）或溶剂预处理EC单层24 h，记录跨内皮电阻（TER）测量值作为屏障完整性的实时评估。在单独的实验中，用氟哌啶醇（10 µM）预处理在Transwell插入物中生长的EC单层，然后用凝血酶（1 U/mL，1 h）刺激并测量FITC-葡聚糖通量。氟哌啶醇显著增加了claudin-5、occludin和ZO-1的表达水平。TER和FITC-葡聚糖Transwell通量的测量证实了与氟哌啶醇治疗相关的凝血酶诱导的屏障破坏的显著衰减。最后，在气管内施用LPS（1.25 mg/kg，16 h）之前用氟哌啶醇（4 mg/kg，IP）预处理的小鼠具有增加的肺紧密连接蛋白-5表达和减少的肺损伤，如通过支气管肺泡灌洗液（BAL）流体蛋白含量、总细胞计数和炎性细胞因子以及肺组织学所评估的。我们的数据证实，氟哌啶醇导致claudin-5表达水平增加，并在体外和体内小鼠ALI模型中显示肺血管保护作用。这些结果表明，氟哌啶醇可能是一种新的治疗方法，用于预防或治疗急性肺损伤，并值得在此背景下进一步调查。
We previously reported that claudin-5, a tight junctional protein, mediates lung vascular permeability in a murine model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Recently, it has been reported that haloperidol, an antipsychotic medication, dose-dependently increases expression of claudin-5 in vitro and in vivo, in brain endothelium. Notably, claudin-5 is highly expressed in both brain and lung tissues. However, the effects of haloperidol on EC barrier function are unknown. We hypothesized that haloperidol increases lung EC claudin-5 expression and attenuates agonist-induced lung EC barrier disruption. Human pulmonary artery ECs were pretreated with haloperidol at variable concentrations (0.1–10 μM) for 24 h. Cell lysates were subjected to Western blotting for claudin-5, in addition to occludin and zona occludens-1 (ZO-1), two other tight junctional proteins. To assess effects on barrier function, EC monolayers were pretreated for 24 h with haloperidol (10 µM) or vehicle prior to treatment with thrombin (1 U/mL), with measurements of transendothelial electrical resistance (TER) recorded as a real-time assessment of barrier integrity. In separate experiments, EC monolayers grown in Transwell inserts were pretreated with haloperidol (10 µM) prior to stimulation with thrombin (1 U/mL, 1 h) and measurement of FITC-dextran flux. Haloperidol significantly increased claudin-5, occludin, and ZO-1 expression levels. Measurements of TER and FITC-dextran Transwell flux confirmed a significant attenuation of thrombin-induced barrier disruption associated with haloperidol treatment. Finally, mice pretreated with haloperidol (4 mg/kg, IP) prior to the intratracheal administration of LPS (1.25 mg/kg, 16 h) had increased lung claudin-5 expression with decreased lung injury as assessed by bronchoalveolar lavage (BAL) fluid protein content, total cell counts, and inflammatory cytokines, in addition to lung histology. Our data confirm that haloperidol results in increased claudin-5 expression levels and demonstrates lung vascular-protective effects both in vitro and in vivo in a murine ALI model. These findings suggest that haloperidol may represent a novel therapy for the prevention or treatment of ALI and warrants further investigation in this context.
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影响因子：
5.8
作者：
Qi D;He J;Wang D;Deng W;Zhao Y;Ye Y;Feng L
通讯作者：
Feng L
影响因子：
7.8
作者：
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通讯作者：
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DOI：
10.1083/jcb.147.1.185
发表时间：
1999-10-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Morita K;Sasaki H;Furuse M;Tsukita S
通讯作者：
Tsukita S
影响因子：
2.8
作者：
Crowley, J. J.;Adkins, D. E.;Sullivan, P. F.
通讯作者：
Sullivan, P. F.
影响因子：
11
作者：
Greene C;Kealy J;Humphries MM;Gong Y;Hou J;Hudson N;Cassidy LM;Martiniano R;Shashi V;Hooper SR;Grant GA;Kenna PF;Norris K;Callaghan CK;Islam MD;O'Mara SM;Najda Z;Campbell SG;Pachter JS;Thomas J;Williams NM;Humphries P;Murphy KC;Campbell M
通讯作者：
Campbell M