Endothelial Dysfunction and Claudin 5 Regulation during Acrolein-Induced Lung Injury

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219-3130, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 04/2011; 44(4):483-90. DOI: 10.1165/rcmb.2009-0391OC
Source: PubMed


An integral membrane protein, Claudin 5 (CLDN5), is a critical component of endothelial tight junctions that control pericellular permeability. Breaching of endothelial barriers is a key event in the development of pulmonary edema during acute lung injury (ALI). A major irritant in smoke, acrolein can induce ALI possibly by altering CLDN5 expression. This study sought to determine the cell signaling mechanism controlling endothelial CLDN5 expression during ALI. To assess susceptibility, 12 mouse strains were exposed to acrolein (10 ppm, 24 h), and survival monitored. Histology, lavage protein, and CLDN5 transcripts were measured in the lung of the most sensitive and resistant strains. CLDN5 transcripts and phosphorylation status of forkhead box O1 (FOXO1) and catenin (cadherin-associated protein) beta 1 (CTNNB1) proteins were determined in control and acrolein-treated human endothelial cells. Mean survival time (MST) varied more than 2-fold among strains with the susceptible (BALB/cByJ) and resistant (129X1/SvJ) strains (MST, 17.3 ± 1.9 h vs. 41.4 ± 5.1 h, respectively). Histological analysis revealed earlier perivascular enlargement in the BALB/cByJ than in 129X1/SvJ mouse lung. Lung CLDN5 transcript and protein increased more in the resistant strain than in the susceptible strain. In human endothelial cells, 30 nM acrolein increased CLDN5 transcripts and increased p-FOXO1 protein levels. The phosphatidylinositol 3-kinase inhibitor LY294002 diminished the acrolein-induced increased CLDN5 transcript. Acrolein (300 nM) decreased CLDN5 transcripts, which were accompanied by increased FOXO1 and CTNNB1. The phosphorylation status of these transcription factors was consistent with the observed CLDN5 alteration. Preservation of endothelial CLDN5 may be a novel clinical approach for ALI therapy.

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Available from: Peter Di, Oct 06, 2015
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    • "A major irritant in smoke, acrolein, can induce acute lung injury, perhaps by altering CLDN5 expression. The phosphorylation status of the FOXO1 and CTNNB1 transcription factors is consistent with the observed alteration in CLDN5 expression.34 Thus, preservation of endothelial CLDN5 may be a novel clinical approach to treatment of acute lung injury.34 "
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    • " , which can promote barrier function via Smo and Gli - 1 ( Kasperczyk et al . , 2009 ) . Finally , Foxo1 is a transcription factor that downregulates claudin - 5 expression , however such mechanism is subject to a remarkable level of transcriptional regulation as cytoplasmic VE - cadherin and b - catenin can independently repress Foxo1 activity ( Jang et al . , 2011 ; Kamo et al . , 2013 ; Taddei et al . , 2008 ) . Taken together , available information suggest that NF - jB and Snail might be dominant negative regulators of BBB functioning , while the Wnt and Hh signal - ing pathways as well as Nrf - 2 and ERG appear to be domi - nant promoters , or at least facilitators , of an optimal BBB phenoty"
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    • "Similarly, degradation of claudin-5 was associated with an increase in dermal microvascular permeability in an in vitro model of malaria [16] and knockdown of claudin-5 in human umbilical vein endothelium caused a decrease in endothelial monolayer electrical resistance [17]. In a mouse model of ALI, a compensatory increase in claudin-5 levels was observed in mice that were resistant to vascular leak [18]. Taken together, these results suggest that claudin-5 is important in regulating endothelial permeability. "
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