Endothelial dysfunction and claudin 5 regulation during acrolein-induced lung injury.
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.
Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219-3130, USA.
An Soo
AS
Jang
Vincent J
VJ
Concel
Kiflai
K
Bein
Kelly A
KA
Brant
Shannen
S
Liu
Hannah
H
Pope-Varsalona
Richard A
RA
Dopico
Y P Peter
YP
Di
Daren L
DL
Knoell
Aaron
A
Barchowsky
George D
GD
Leikauf
D000171:Acrolein; D000818:Animals; D002460:Cell Line; D062507:Claudin-5; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055806:Microvessels / Q000166:cytology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D051176:beta Catenin / Q000378:metabolism
C107466:CLDN5 protein, human; D062507:Claudin-5; C491511:Cldn5 protein, mouse; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051176:beta Catenin; D000171:Acrolein; D058539:Phosphatidylinositol 3-Kinase