Endothelial Dysfunction And Claudin 5 Regulation During Acrolein-induced Lung Injury

Jang, An‐Soo; Concel, Vincent J.; Bein, Kiflai; Brant, Kelly A.; Liu, Shannen; Pope-Varsalona, Hannah; Dopico, Richard A.; Di, Yao; Barchowsky, Aaron; Leikauf, George D.

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a3607

Cited by 11 publications

(22 citation statements)

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“…It is known that elevated levels of plasma homocysteine cause a decrease in Cldn5 expression in BMVECs, through a mechanism involving the nuclear translocation of b-catenin and the binding of this protein to the putative Cldn5 repressor (Beard et al, 2011). This mechanism has also been reported in LMVECs in response to acrolein-induced lung injury (Jang et al, 2011). Furthermore, IL1b has been shown to act in conjunction with tobacco smoke in mouse cardiac endothelial cells to induce the disassembly of the adherens junction complexes and the subsequent translocation of b-catenin to the nucleus (Barbieri et al, 2008;Barbieri and Weksler, 2007).…”

Section: Discussionsupporting

confidence: 54%

“…This and other mechanisms for the upregulation of tight junctions have been explored mainly in the developing endothelium as opposed to in mature endothelium responding to external stimuli. Evidence is emerging that this mechanism for Cldn5 regulation can be reversed in response to pathologic stimuli, such as in hyperhomocysteinemia (Beard et al, 2011) and acrolein-induced acute lung injury (Jang et al, 2011). In addition, it has been demonstrated that IL-1b signaling leads to downregulation of Cldn5 expression at the BBB, particularly after mild ischemic brain injury in mice (McColl et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells

Beard

Haines

et al. 2014

Journal of Cell Science

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Aberrant elevation in the levels of the pro-inflammatory cytokine interleukin-1b (IL-1b) contributes to neuroinflammatory diseases. Blood-brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation. It is known that IL-1b directly induces BBB hyperpermeability but the mechanisms remain unclear. Claudin-5 (Cldn5) is a tight junction protein found at endothelial cell-cell contacts that are crucial for maintaining brain microvascular endothelial cell (BMVEC) integrity. Transcriptional regulation of Cldn5 has been attributed to the transcription factors b-catenin and forkhead box protein O1 (FoxO1), and the signaling molecules regulating their nuclear translocation. Non-muscle myosin light chain kinase (nmMlck, encoded by the Mylk gene) is a key regulator involved in endothelial hyperpermeability, and IL-1b has been shown to mediate nmMlck-dependent barrier dysfunction in epithelia. Considering these factors, we tested the hypothesis that nmMlck modulates IL-1b-mediated downregulation of Cldn5 in BMVECs in a manner that depends on transcriptional repression mediated by b-catenin and FoxO1. We found that treating BMVECs with IL-1b induced barrier dysfunction concomitantly with the nuclear translocation of b-catenin and FoxO1 and the repression of Cldn5. Most importantly, using primary BMVECs isolated from mice null for nmMlck, we identified that Cldn5 repression caused by b-catenin and FoxO1 in IL-1b-mediated barrier dysfunction was dependent on nmMlck.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells

Beard

Haines

et al. 2014

Journal of Cell Science

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“…Acrolein (2-propenal) is a highly reactive α, β-unsaturated aldehyde and a respiratory irritant that is ubiquitously present in the environment but that can also be generated endogenously at sites of inflammation [1,2] . Acrolein is abundant in tobacco smoke, which is the major environmental risk factor for asthma and chronic obstructive pulmonary disease (COPD), and elevated levels of acrolein are found in the lung fluids of asthma and COPD patients [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

“…Acrolein is abundant in tobacco smoke, which is the major environmental risk factor for asthma and chronic obstructive pulmonary disease (COPD), and elevated levels of acrolein are found in the lung fluids of asthma and COPD patients [1][2][3]. Because of its reactivity with respiratory-lining fluid or cellular macromolecules, acrolein alters gene regulation, inflammation, mucociliary transport, and alveolar-capillary barrier integrity [1].…”

Section: Introductionmentioning

confidence: 99%

“…An integral membrane protein, Claudin 5 (CLDN5), is a critical component of endothelial tight junctions that control pericellular permeability [2]. Acrolein can induce ALI with perivascular edema in mice, accompanying by a compensatory increase in CLDN5 transcript and protein, which was more evident in a resistant than a sensitive mouse strain [2].…”

Section: Introductionmentioning

confidence: 99%

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Claudin 5 Transcripts Following Acrolein Exposure Affected by Epigenetic Enzyme

Moon¹,

Lee²,

Kim³

et al. 2015

J Clin Toxicol

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Background and objective: Acrolein is a highly reactive α, β-unsaturated aldehyde and a respiratory irritant that is ubiquitously present in the environment but that can also be generated endogenously at sites of inflammation. Apical junctional protein claudin 5 can be affected by acrolein. This study aimed to determine the impact of aberrant expression of DNMT1, DNMT3b, MBD3, and MeCP2 on acrolein induced claudin 5.

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Acrolein – a pulmonary hazard

Bein

Leikauf

2011

Molecular Nutrition Food Res

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Acrolein is a respiratory irritant that can be generated during cooking and is in environmental tobacco smoke. More plentiful in cigarette smoke than polycyclic aromatic hydrocarbons (PAH), acrolein can adduct tumor suppressor p53 (TP53) DNA and may contribute to TP53-mutations in lung cancer. Acrolein is also generated endogenously at sites of injury, and excessive breath levels (sufficient to activate metalloproteinases and increase mucin transcripts) have been detected in asthma and chronic obstructive pulmonary disease (COPD). Because of its reactivity with respiratory-lining fluid or cellular macromolecules, acrolein alters gene regulation, inflammation, mucociliary transport, and alveolar-capillary barrier integrity. In laboratory animals, acute exposures have lead to acute lung injury and pulmonary edema similar to that produced by smoke inhalation whereas lower concentrations have produced bronchial hyperreactivity, excessive mucus production, and alveolar enlargement. Susceptibility to acrolein exposure is associated with differential regulation of cell surface receptor, transcription factor, and ubiquitin-proteasome genes. Consequent to its pathophysiological impact, acrolein contributes to the morbidly and mortality associated with acute lung injury and COPD, and possibly asthma and lung cancer.

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Endothelial Dysfunction And Claudin 5 Regulation During Acrolein-induced Lung Injury

Cited by 11 publications

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Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells

Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells

Claudin 5 Transcripts Following Acrolein Exposure Affected by Epigenetic Enzyme

Acrolein – a pulmonary hazard

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