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Haloperidol Attenuates Lung Endothelial Cell Permeability In Vitro and In Vivo

Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois Chicago, Chicago, IL 60607, USA
Room 920N (MC719), 840 S. Wood St., Chicago, IL 60612, USA
Author to whom correspondence should be addressed.
Academic Editor: Konstantin G. Birukov
Cells 2021, 10(9), 2186;
Received: 19 May 2021 / Revised: 18 July 2021 / Accepted: 24 July 2021 / Published: 25 August 2021
(This article belongs to the Collection The Endothelial Cell in Lung Inflammation)
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. View Full-Text
Keywords: haloperidol; claudin-5; endothelial cells; vascular permeability; acute lung injury haloperidol; claudin-5; endothelial cells; vascular permeability; acute lung injury
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MDPI and ACS Style

Colamonici, M.A.; Epshtein, Y.; Chen, W.; Jacobson, J.R. Haloperidol Attenuates Lung Endothelial Cell Permeability In Vitro and In Vivo. Cells 2021, 10, 2186.

AMA Style

Colamonici MA, Epshtein Y, Chen W, Jacobson JR. Haloperidol Attenuates Lung Endothelial Cell Permeability In Vitro and In Vivo. Cells. 2021; 10(9):2186.

Chicago/Turabian Style

Colamonici, Marco A., Yulia Epshtein, Weiguo Chen, and Jeffrey R. Jacobson. 2021. "Haloperidol Attenuates Lung Endothelial Cell Permeability In Vitro and In Vivo" Cells 10, no. 9: 2186.

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