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.