Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappaB 1 1Abbreviations: A549 cells, human alveolar epithelial type II cell line; AP-1, activator protein-1; BSO; dl-buthionine (SR)-sulfoximine; COPD, chronic obstructive pulmonary disease; DMEM, Dulbecco’s modified Eagle’s medium; DTT, dithiothreitol; GSHMEE, glutathione monoethyl ester; H2O2, hydrogen peroxide; IkB, inhibitory binding protein kB; LDH, lactic dehydrogenase; NAC, N-acetyl-l-cysteine;

Rahman, Irfan; Mulier, Brigitte; Gilmour, Peter S.; Watchorn, Tammy; Donaldson, Kenneth; Jeffery, Peter K.; MacNee, William

doi:10.1016/s0006-2952(01)00702-x

Cited by 117 publications

(15 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxidative stress is a harmful process that leads to airway and lung damage and, consequently, to severe respiratory diseases [22]. ROS induce the expression of the genes of inflammatory mediators, such as TNF- α and IL-1 β [23, 24], in bronchial epithelial cells and can eventually cause pulmonary epithelial dysfunction [8, 25]. …”

Section: Discussionmentioning

confidence: 99%

Krüppel-Like Factor 5 Mediates Proinflammatory Cytokine Expression in Lipopolysaccharide-Induced Acute Lung Injury through Upregulation of Nuclear Factor-κB PhosphorylationIn VitroandIn Vivo

Chen

Chong

Lee

et al. 2014

Mediators of Inflammation

View full text Add to dashboard Cite

Acute lung injury (ALI) is associated with an inflammation-mediated process, and the transcription factor, Krüppel-like factor 5 (KLF5), might play a crucial role in inflammatory lung disease. In this study, we evaluated KLF5, reactive oxygen species (ROS), and inflammatory responses in a lipopolysaccharide- (LPS-) induced ALI model to elucidate the role of KLF5 in ALI. Our data indicated that LPS upregulates proinflammatory cytokine expression in human bronchial epithelial cells in a dose-dependent manner. We observed upregulated KLF5 protein expression in human bronchial epithelial cells exposed to LPS, with peak expression 1 h after LPS treatment, and subsequent upregulation of p65 protein expression and p65 phosphorylation at Ser276. These results indicate that KLF5 mediates proinflammatory cytokine expression by upregulating nuclear factor-kappaB (NF-κB) phosphorylation at p65 in response to LPS. LPS treatment also increased ROS production and simultaneously upregulated KLF5 expression and NF-κB translocation. N-acetylcysteine significantly reduced ROS levels and KLF5 and NF-κB translocation in nuclear extracts. Therefore, N-acetylcysteine pretreatment before LPS exposure reduces ROS, downregulates KLF5 expression, and subsequently reduces inflammatory responses by scavenging ROS. Overall, our study results indicate that KLF5 mediates proinflammatory cytokine expression through upregulation of NF-κB phosphorylation at p65 in LPS-induced ALI.

show abstract

Section: Discussionmentioning

confidence: 99%

Krüppel-Like Factor 5 Mediates Proinflammatory Cytokine Expression in Lipopolysaccharide-Induced Acute Lung Injury through Upregulation of Nuclear Factor-κB PhosphorylationIn VitroandIn Vivo

Chen

Chong

Lee

et al. 2014

Mediators of Inflammation

View full text Add to dashboard Cite

show abstract

“…In line with these observations, we also did not observe any effect of the macrophage supernatants on NF-κB pathway activation in RLE cells upon modification of the intracellular glutathione content with BSO or NAC. In alveolar epithelial cells, glutathione is considered to be the most important intracellular antioxidant [52]. Lower levels of intracellular glutathione have been associated with enhanced NF-κB activation [53].…”

Section: Discussionmentioning

confidence: 99%

NF-κB dependent and independent mechanisms of quartz-induced proinflammatory activation of lung epithelial cells

et al. 2010

View full text Add to dashboard Cite

In the initiation and progression of pulmonary inflammation, macrophages have classically been considered as a crucial cell type. However, evidence for the role of epithelial type II cells in pulmonary inflammation has been accumulating. In the current study, a combined in vivo and in vitro approach has been employed to investigate the mechanisms of quartz-induced proinflammatory activation of lung epithelial cells. In vivo, enhanced expression of the inflammation- and oxidative stress-related genes HO-1 and iNOS was found on the mRNA level in rat lungs after instillation with DQ12 respirable quartz. Activation of the classical NF-κB pathway in macrophages and type II pneumocytes was indicated by enhanced immunostaining of phospho-IκBα in these specific lung cell types. In vitro, the direct, particle-mediated effect on proinflammatory signalling in a rat lung epithelial (RLE) cell line was compared to the indirect, macrophage product-mediated effect. Treatment with quartz particles induced HO-1 and COX-2 mRNA expression in RLE cells in an NF-κB independent manner. Supernatant from quartz-treated macrophages rapidly activated the NF-κB signalling pathway in RLE cells and markedly induced iNOS mRNA expression up to 2000-fold compared to non-treated control cells. Neutralisation of TNFα and IL-1β in macrophage supernatant did not reduce its ability to elicit NF-κB activation of RLE cells. In addition the effect was not modified by depletion or supplementation of intracellular glutathione.The results from the current work suggest that although both oxidative stress and NF-κB are likely involved in the inflammatory effects of toxic respirable particles, these phenomena can operate independently on the cellular level. This might have consequences for in vitro particle hazard testing, since by focusing on NF-κB signalling one might neglect alternative inflammatory pathways.

show abstract

“…It is well established that oxidative stress in airway epithelium stimulates and initiates a molecular signal cascade leading to the activation of NF-κB [35], [36] which translocates to the nucleus. In the nucleus NF-κB binds to DNA and transcribes inflammatory markers such as interleukin (IL)-6, IL-8, macrophage inflammatory protein 2 (MIP-2), granulocyte macrophage colony-stimulating factor (GM-CSF), intercellular adhesion molecule-1 (ICAM-1), COX-2 and iNOS, which besides directly causing inflammation also promote inflammatory cells infiltration [37]–[42].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Aldose Reductase Prevents Experimental Allergic Airway Inflammation in Mice

Yadav¹,

Ramana²,

Aguilera-Aguirre

et al. 2009

PLoS ONE

View full text Add to dashboard Cite

BackgroundThe bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR), contributes to the pathogenesis of oxidative stress–induced inflammation by affecting the NF-κB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma.Methods and FindingsPrimary Human Small Airway Epithelial Cells (SAEC) were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE)-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-κB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS), cycloxygenase (COX)-2, Prostaglandin (PG) E2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results indicate that inhibition of AR prevents airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid and airway hyperresponsiveness in mice.ConclusionsThese results suggest that airway inflammation due to allergic response to RWE, which subsequently activates oxidative stress-induced expression of inflammatory cytokines via NF-κB-dependent mechanism, could be prevented by AR inhibitors. Therefore, inhibition of AR could have clinical implications, especially for the treatment of airway inflammation, a major cause of asthma pathogenesis.

show abstract

Cited by 117 publications

References 31 publications

Krüppel-Like Factor 5 Mediates Proinflammatory Cytokine Expression in Lipopolysaccharide-Induced Acute Lung Injury through Upregulation of Nuclear Factor-κB PhosphorylationIn VitroandIn Vivo

Krüppel-Like Factor 5 Mediates Proinflammatory Cytokine Expression in Lipopolysaccharide-Induced Acute Lung Injury through Upregulation of Nuclear Factor-κB PhosphorylationIn VitroandIn Vivo

NF-κB dependent and independent mechanisms of quartz-induced proinflammatory activation of lung epithelial cells

Inhibition of Aldose Reductase Prevents Experimental Allergic Airway Inflammation in Mice

Contact Info

Product

Resources

About