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

Abstract

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.

Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures

“…We have identified acrolein as putative mediator for nicotine-independent toxicity on the basis of its presence in both e-Cig solution and vapor and on a large body of literature showing adverse pulmonary effects of acrolein, including on endothelial intercellular tethering molecules (12). The signaling effects on nicotine-free e-Cig vapors on the lung endothelial barrier remain to be investigated.…”

Structural and biochemical abnormalities in the absence of acute deficits in mild primary blast-induced head trauma

“…One critical piece of evidence supporting such a notion is that acrolein exposure can lead to destruction of claudin-5 (CLDN5), a critical component of BBB tight junctions. 6,39,54 Furthermore, CLDN5 has recently been shown to be absent from brain microvasculature in the hours following BINT. 1 …”

Molecular pathology of pulmonary edema in forensic autopsy cases with special regard to fatal hyperthermia and hypothermia

“…These different expression patterns of MMPs suggest partly overlapping and independent contributions of MMP-2 and MMP-9 to alveolar damage in hyperthermia and hypothermia, involving degradation of ECM components of the basement membrane and interstitium by MMPs [18,31], which need further investigation. In hyperthermia, furthermore, up-regulated mRNA CNRQ values of intrapulmonary ICAM-1 and CLDN-5 suggest responses to the damage of alveolar epithelia and vascular endothelia [32], and alveolar endothelial tight junction [33], respectively, which may increase vascular permeability and induce pulmonary edema.…”