scholarly journals Lung Epithelial TRPA1 Transduces the Extracellular ROS into Transcriptional Regulation of Lung Inflammation Induced by Cigarette Smoke: The Role of Influxed Ca2+

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
An-Hsuan Lin ◽  
Meng-Han Liu ◽  
Hsin-Kuo Ko ◽  
Diahn-Warng Perng ◽  
Tzong-Shyuan Lee ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Cigarette Smoke ◽  
Lung Inflammation ◽  
Lung Epithelial Cells ◽  
Wild Type ◽  
Intracellular Ros ◽  
Lung Epithelial ◽  
Intracellular Ca ◽  
Acetyl Cysteine

The mechanism underlying the inflammatory role of TRPA1 in lung epithelial cells (LECs) remains unclear. Here, we show that cigarette smoke extract (CSE) sequentially induced several events in LECs. The Ca2+influx was prevented by decreasing extracellular reactive oxygen species (ROS) with the scavenger N-acetyl-cysteine, removing extracellular Ca2+with the chelator EGTA, or treating with the TRPA1 antagonist HC030031. NADPH oxidase activation was abolished by its inhibitor apocynin, EGTA, or HC030031. The increased intracellular ROS was halted by apocynin, N-acetyl-cysteine, or HC030031. The activation of the MAPKs/NF-κB signaling was suppressed by EGTA, N-acetyl-cysteine, or HC030031. IL-8 induction was inhibited by HC030031 or TRPA1 siRNA. Additionally, chronic cigarette smoke (CS) exposure in wild-type mice induced TRPA1 expression in LECs and lung tissues. In CS-exposuretrpa1−/−mice, the increased BALF level of ROS was similar to that of CS-exposure wild-type mice; yet lung inflammation was lessened. Thus, in LECs, CSE may initially increase extracellular ROS, which activate TRPA1 leading to an increase in Ca2+influx. The increased intracellular Ca2+contributes to activation of NADPH oxidase, resulting in increased intracellular ROS, which activate the MAPKs/NF-κB signaling leading to IL-8 induction. This mechanism may possibly be at work in mice chronically exposed to CS.

scholarly journals Impaired Pulmonary NF-κB Activation in Response to Lipopolysaccharide in NADPH Oxidase-Deficient Mice

2001 ◽  
Vol 69 (10) ◽  
pp. 5991-5996 ◽  
Author(s):  
M. Audrey Koay ◽  
John W. Christman ◽  
Brahm H. Segal ◽  
Annapurna Venkatakrishnan ◽  
Thomas R. Blackwell ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Intracellular Signaling ◽  
Lung Inflammation ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Wild Type ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Deficient Mice

ABSTRACT Reactive oxygen species (ROS) are thought to be involved in intracellular signaling, including activation of the transcription factor NF-κB. We investigated the role of NADPH oxidase in the NF-κB activation pathway by utilizing knockout mice (p47phox−/−) lacking the p47phox component of NADPH oxidase. Wild-type (WT) controls and p47phox−/−mice were treated with intraperitoneal (i.p.) Escherichia coli lipopolysaccharide (LPS) (5 or 20 μg/g of body weight). LPS-induced NF-κB binding activity and accumulation of RelA in nuclear protein extracts of lung tissue were markedly increased in WT compared to p47phox−/− mice 90 min after treatment with 20 but not 5 μg of i.p. LPS per g. In another model of lung inflammation, RelA nuclear translocation was reduced in p47phox−/− mice compared to WT mice following treatment with aerosolized LPS. In contrast to NF-κB activation in p47phox−/− mice, LPS-induced production of macrophage inflammatory protein 2 in the lungs and neutrophilic lung inflammation were not diminished in these mice compared to WT mice. We conclude that LPS-induced NF-κB activation is deficient in the lungs of p47phox−/− mice compared to WT mice, but this abnormality does not result in overt alteration in the acute inflammatory response.

scholarly journals IL-35 subunit EBI3 alleviates bleomycin-induced pulmonary fibrosis via suppressing DNA enrichment of STAT3

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Donghong Chen ◽  
Guofeng Zheng ◽  
Qing Yang ◽  
Le Luo ◽  
Jinglian Shen
Keyword(s):  
Gene Expression ◽  
Pulmonary Fibrosis ◽  
Regulatory Mechanism ◽  
Lung Epithelial Cells ◽  
Wild Type ◽  
Qrt Pcr ◽  
Lung Epithelial ◽  
Gene Expression Analyses ◽  
Human And Mouse

Abstract Background IL-35 subunit EBI3 is up-regulated in pulmonary fibrosis tissues. In this study, we investigated the pathological role of EBI3 in pulmonary fibrosis and dissected the underlying molecular mechanism. Methods Bleomycin-induced pulmonary fibrosis mouse model was established, and samples were performed gene expression analyses through RNAseq, qRT-PCR and Western blot. Wild type and EBI3 knockout mice were exposed to bleomycin to investigate the pathological role of IL-35, via lung function and gene expression analyses. Primary lung epithelial cells were used to dissect the regulatory mechanism of EBI3 on STAT1/STAT4 and STAT3. Results IL-35 was elevated in both human and mouse with pulmonary fibrosis. EBI3 knockdown aggravated the symptoms of pulmonary fibrosis in mice. EBI3 deficiency enhanced the expressions of fibrotic and extracellular matrix-associated genes. Mechanistically, IL-35 activated STAT1 and STAT4, which in turn suppressed DNA enrichment of STAT3 and inhibited the fibrosis process. Conclusion IL-35 might be one of the potential therapeutic targets for bleomycin-induced pulmonary fibrosis.

The role of oxidative stress in the biological responses of lung epithelial cells to cigarette smoke

Biomarkers ◽  
2009 ◽  
Vol 14 (sup1) ◽  
pp. 90-96 ◽  
Author(s):  
Stephen P. Faux ◽  
Teresa Tai ◽  
David Thorne ◽  
Yong Xu ◽  
Damien Breheny ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Lung Epithelial Cells ◽  
Biological Responses ◽  
Lung Epithelial

SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice

2013 ◽  
Vol 305 (12) ◽  
pp. L981-L989 ◽  
Author(s):  
Tiziana P. Cremona ◽  
Stefan A. Tschanz ◽  
Christophe von Garnier ◽  
Charaf Benarafa
Keyword(s):  
Cigarette Smoke ◽  
Serine Proteases ◽  
Lung Epithelial Cells ◽  
Cathepsin G ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Adult Mice ◽  
Age Related ◽  
Lung Epithelial

Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and chronic bronchitis and is a leading cause of morbidity and mortality worldwide. Tobacco smoke and deficiency in α1-antitrypsin (AAT) are the most prominent environmental and genetic risk factors, respectively. Yet the pathogenesis of COPD is not completely elucidated. Disease progression appears to include a vicious circle driven by self-perpetuating lung inflammation, endothelial and epithelial cell death, and proteolytic degradation of extracellular matrix proteins. Like AAT, serpinB1 is a potent inhibitor of serine proteases including neutrophil elastase and cathepsin G. Because serpinB1 is expressed in myeloid and lung epithelial cells and is protective during lung infections, we investigated the role of serpinB1 in preventing age-related and cigarette smoke-induced emphysema in mice. Fifteen-month-old mice showed increased lung volume and decreased pulmonary function compared with young adult mice (3 mo old), but no differences were observed between serpinB1-deficient (KO) and wild-type (WT) mice. Chronic exposure to secondhand cigarette smoke resulted in structural emphysematous changes compared with respective control mice, but no difference in lung morphometry was observed between genotypes. Of note, the different pattern of stereological changes induced by age and cigarette smoke suggest distinct mechanisms leading to increased airway volume. Finally, expression of intracellular and extracellular protease inhibitors were differently regulated in lungs of WT and KO mice following smoke exposure; however, activity of proteases was not significantly altered. In conclusion, we showed that, although AAT and serpinB1 are similarly potent inhibitors of neutrophil proteases, serpinB1 deficiency is not associated with more severe emphysema.

scholarly journals Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice

2008 ◽  
Vol 172 (5) ◽  
pp. 1222-1237 ◽  
Author(s):  
Hongwei Yao ◽  
Indika Edirisinghe ◽  
Se-Ran Yang ◽  
Saravanan Rajendrasozhan ◽  
Aruna Kode ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Cigarette Smoke ◽  
Lung Inflammation ◽  
Genetic Ablation

MC1568 inhibits HDAC6/8 activity and influenza A virus replication in lung epithelial cells: role of Hsp90 acetylation

2016 ◽  
Vol 8 (17) ◽  
pp. 2017-2031 ◽  
Author(s):  
Simona Panella ◽  
Maria Elena Marcocci ◽  
Ignacio Celestino ◽  
Sergio Valente ◽  
Clemens Zwergel ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor

2001 ◽  
Vol 280 (2) ◽  
pp. L316-L325 ◽  
Author(s):  
Kazuyoshi Kuwano ◽  
Ritsuko Kunitake ◽  
Takashige Maeyama ◽  
Naoki Hagimoto ◽  
Masayuki Kawasaki ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Inflammation ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Inflammatory Cells ◽  
Lung Epithelial Cells ◽  
Caspase Inhibitor ◽  
Hydroxyproline Content ◽  
Caspase 1 ◽  
Lung Epithelial

Caspases have been implicated in the effector process of apoptosis in several systems including the Fas-Fas ligand pathway. We previously demonstrated that excessive apoptosis of lung epithelial cells and the Fas-Fas ligand pathway were essential in the pathogenesis of bleomycin-induced pneumopathy in mice. Therefore, the purpose of this study was to investigate whether a caspase inhibitor could prevent the development of this model. The expression of caspase-1 and caspase-3 was upregulated on lung epithelial cells, alveolar macrophages, and infiltrating inflammatory cells in this model. We demonstrated that a broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, decreased the caspase-1- and caspase-3-like activity, the number of apoptotic cells, the pathological grade of lung inflammation and fibrosis, and the hydroxyproline content in lung tissues in this model. We conclude that caspase inhibitors could be a new therapeutic approach against lung injury and pulmonary fibrosis.

scholarly journals HIV-1 Productively Infects and Integrates in Bronchial Epithelial Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
Dinesh Devadoss ◽  
Shashi P. Singh ◽  
Arpan Acharya ◽  
Kieu Chinh Do ◽  
Palsamy Periyasamy ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Lung Epithelial Cells ◽  
People Living With Hiv ◽  
Sequencing Analysis ◽  
Hiv Reservoirs ◽  
Bronchial Epithelial ◽  
Lung Epithelial ◽  
Hiv 1

BackgroundThe role of lung epithelial cells in HIV-1-related lung comorbidities remains unclear, and the major hurdle in curing HIV is the persistence of latent HIV reservoirs in people living with HIV (PLWH). The advent of combined antiretroviral therapy has considerably increased the life span; however, the incidence of chronic lung diseases is significantly higher among PLWH. Lung epithelial cells orchestrate the respiratory immune responses and whether these cells are productively infected by HIV-1 is debatable.MethodsNormal human bronchial epithelial cells (NHBEs) grown on air–liquid interface were infected with X4-tropic HIV-1LAV and examined for latency using latency-reversing agents (LRAs). The role of CD4 and CXCR4 HIV coreceptors in NHBEs were tested, and DNA sequencing analysis was used to analyze the genomic integration of HIV proviral genes, Alu-HIVgag-pol, HIV-nef, and HIV-LTR. Lung epithelial sections from HIV-infected humans and SHIV-infected macaques were analyzed by FISH for HIV-gag-pol RNA and epithelial cell-specific immunostaining.Results and DiscussionNHBEs express CD4 and CXCR4 at higher levels than A549 cells. NHBEs are infected with HIV-1 basolaterally, but not apically, by X4-tropic HIV-1LAV in a CXCR4/CD4-dependent manner leading to HIV-p24 antigen production; however, NHBEs are induced to express CCR5 by IL-13 treatment. In the presence of cART, HIV-1 induces latency and integration of HIV provirus in the cellular DNA, which is rescued by the LRAs (endotoxin/vorinostat). Furthermore, lung epithelial cells from HIV-infected humans and SHIV-infected macaques contain HIV-specific RNA transcripts. Thus, lung epithelial cells are targeted by HIV-1 and could serve as potential HIV reservoirs that may contribute to the respiratory comorbidities in PLWH.

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