Noxa ReducesBcl-2mRNA Half-Life To Mediate Cell Death in Hyperplastic Airway Epithelial Cells.

2009 ◽  
Author(s):  
N Singh ◽  
Y Tesfaigzi
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Half Life ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mediate Cell

Effects of Minocycline on H2O2-induced Cell Death and Interleukin-8 Production in Human Small Airway Epithelial Cells

2019 ◽  
Vol 15 (4) ◽  
pp. 509-514
Author(s):  
Takahiro Sato ◽  
Ayano Hirohara ◽  
Yuki Izumi ◽  
Takayuki Nakatomi ◽  
Kuninori Iwayama ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Small Airway ◽  
Interleukin 8 ◽  
Airway Epithelial ◽  
Small Airway Epithelial Cells

scholarly journals Human Parvovirus Infection of Human Airway Epithelia Induces Pyroptotic Cell Death by Inhibiting Apoptosis

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Xuefeng Deng ◽  
Wei Zou ◽  
Min Xiong ◽  
Zekun Wang ◽  
John F. Engelhardt ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Human Bocavirus ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Human Airway ◽  
Caspase 1 ◽  
Tract Infections ◽  
Human Airway Epithelia

ABSTRACT Human bocavirus 1 (HBoV1) is a human parvovirus that causes acute respiratory tract infections in young children. In this study, we confirmed that, when polarized/well-differentiated human airway epithelia are infected with HBoV1 in vitro, they develop damage characterized by barrier function disruption and cell hypotrophy. Cell death mechanism analyses indicated that the infection induced pyroptotic cell death characterized by caspase-1 activation. Unlike infections with other parvoviruses, HBoV1 infection did not activate the apoptotic or necroptotic cell death pathway. When the NLRP3-ASC-caspase-1 inflammasome-induced pathway was inhibited by short hairpin RNA (shRNA), HBoV1-induced cell death dropped significantly; thus, NLRP3 mediated by ASC appears to be the pattern recognition receptor driving HBoV1 infection-induced pyroptosis. HBoV1 infection induced steady increases in the expression of interleukin 1α (IL-1α) and IL-18. HBoV1 infection was also associated with the marked expression of the antiapoptotic genes BIRC5 and IFI6. When the expression of BIRC5 and/or IFI6 was inhibited by shRNA, the infected cells underwent apoptosis rather than pyroptosis, as indicated by increased cleaved caspase-3 levels and the absence of caspase-1. BIRC5 and/or IFI6 gene inhibition also significantly reduced HBoV1 replication. Thus, HBoV1 infection of human airway epithelial cells activates antiapoptotic proteins that suppress apoptosis and promote pyroptosis. This response may have evolved to confer a replicative advantage, thus allowing HBoV1 to establish a persistent airway epithelial infection. This is the first report of pyroptosis in airway epithelia infected by a respiratory virus. IMPORTANCE Microbial infection of immune cells often induces pyroptosis, which is mediated by a cytosolic protein complex called the inflammasome that senses microbial pathogens and then activates the proinflammatory cytokines IL-1 and IL-18. While virus-infected airway epithelia often activate NLRP3 inflammasomes, studies to date suggest that these viruses kill the airway epithelial cells via the apoptotic or necrotic pathway; involvement of the pyroptosis pathway has not been reported previously. Here, we show for the first time that virus infection of human airway epithelia can also induce pyroptosis. Human bocavirus 1 (HBoV1), a human parvovirus, causes lower respiratory tract infections in young children. This study indicates that HBoV1 kills airway epithelial cells by activating genes that suppress apoptosis and thereby promote pyroptosis. This strategy appears to promote HBoV1 replication and may have evolved to allow HBoV1 to establish persistent infection of human airway epithelia.

scholarly journals Increased susceptibility of cystic fibrosis airway epithelial cells to ferroptosis

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Pramila Maniam ◽  
Ama-Tawiah Essilfie ◽  
Murugan Kalimutho ◽  
Dora Ling ◽  
David M. Frazer ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Epithelial Cells ◽  
Lung Disease ◽  
Ferrous Iron ◽  
Airway Epithelial Cells ◽  
Iron Accumulation ◽  
Airway Epithelial ◽  
Increased Susceptibility

Abstract Background Defective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease. Results Here, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator deferoxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane. Conclusion These studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis. Graphical Abstract

scholarly journals Obesity impairs therapeutic efficacy of mesenchymal stem cells by inhibiting cardiolipin-dependent mitophagy and intercellular mitochondrial transfer in mouse models of airway allergic inflammation

2021 ◽  
Author(s):  
Shakti Sagar ◽  
Md. Imam Faizan ◽  
Nisha Chaudhary ◽  
Atish Gheware ◽  
Khushboo Sharma ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Human Subjects ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mitochondrial Transfer ◽  
Metabolic Conditions

Mesenchymal stem cell (MSC) transplantation alleviates metabolic defects in diseased recipient cells by intercellular mitochondrial transport (IMT). However, the effect of host metabolic conditions on MSCs in general, and IMT in particular, has largely remained unexplored. This study has identified a molecular pathway that primarily governs the metabolic function and IMT of MSCs. We found underlying mitochondrial dysfunction, impaired mitophagy, and reduced IMT in MSCs derived from high-fat diet (HFD)-induced obese mice (MSC-Ob). Mechanistically, MSC-Ob failed to sequester their damaged mitochondria into LC3-dependent autophagosomes due to decrease in mitochondrial cardiolipin content, which we propose as a putative mitophagy receptor for LC3 in MSCs. Functionally, MSC-Ob exhibited diminished potential to rescue metabolic deficits and cell death in stress-induced epithelial cells. In a small molecule screen, we found pyrroloquinoline quinone (PQQ) as a regulator of mitophagy and IMT. Long-term culture of MSC-Ob with PQQ (MSC-ObPQQ) restored cardiolipin content and sequestration of mitochondria to autophagosomes with concomitant activation of mitophagy. Upon co-culture, MSC-ObPQQ rescued cell death in stress-induced epithelial cells by enhancing IMT. The beneficial effect of PQQ was also evident in MSCs derived from human subjects in an in vitro model. In two independent mice models, the transplantation of MSC-ObPQQ restored IMT to airway epithelial cells, improved their mitochondrial metabolism and attenuated features of allergic airway inflammation (AAI). However, unmodulated MSC-Ob failed to do so. In summary, we uncover the molecular mechanism leading to the therapeutic decline of obese-derived MSCs and highlight the importance of pharmacological modulation of these cells for therapeutic intervention.

scholarly journals H5N1 Avian Influenza Virus Induces Apoptotic Cell Death in Mammalian Airway Epithelial Cells

2008 ◽  
Vol 82 (22) ◽  
pp. 11294-11307 ◽  
Author(s):  
Tomo Daidoji ◽  
Takaaki Koma ◽  
Anariwa Du ◽  
Cheng-Song Yang ◽  
Mayo Ueda ◽  
...  
Keyword(s):  
Cell Death ◽  
Influenza Virus ◽  
Hong Kong ◽  
Epithelial Cells ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Airway Epithelial Cells ◽  
Influenza Viruses ◽  
Airway Epithelial ◽  
Viral Growth

ABSTRACT In recent years, the highly pathogenic avian influenza virus H5N1 has raised serious worldwide concern about an influenza pandemic; however, the biology of H5N1 pathogenesis is largely unknown. To elucidate the mechanism of H5N1 pathogenesis, we prepared primary airway epithelial cells from alveolar tissues from 1-year-old pigs and measured the growth kinetics of three avian H5 influenza viruses (A/Crow/Kyoto/53/2004 [H5N1], A/Duck/Hong Kong/342/78 [H5N2], and A/Duck/Hong Kong/820/80 [H5N3]), the resultant cytopathicity, and possible associated mechanisms. H5N1, but not the other H5 viruses, strongly induced cell death in porcine alveolar epithelial cells (pAEpC), although all three viruses induced similar degrees of cytopathicity in chicken embryonic fibroblasts. Intracellular viral growth and the production of progeny viruses were comparable in pAEpC infected with each H5 virus. In contrast, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-positive cells were detected only in H5N1-infected pAEpC, and the activities of caspases 3, 8, and 9 were significantly elevated in pAEpC infected with H5N1, but not with H5N2 and H5N3. These results suggest that only H5N1 induces apoptosis in pAEpC. H5N1 cytopathicity was inhibited by adding the caspase inhibitor z-VAD-FMK; however, there were no significant differences in viral growth or release of progeny viruses. Further investigations using reverse genetics demonstrated that H5N1 hemagglutinin protein plays a critical role in inducing caspase-dependent apoptosis in infected pAEpC. H5N1-specific cytopathicity was also observed in human primary airway epithelial cells. Taken together, these data suggest that avian H5N1 influenza virus leads to substantial cell death in mammalian airway epithelial cells due to the induction of apoptosis.

Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation

2014 ◽  
Vol 307 (3) ◽  
pp. L240-L251 ◽  
Author(s):  
M. de Vries ◽  
I. H. Heijink ◽  
R. Gras ◽  
L. E. den Boef ◽  
M. Reinders-Luinge ◽  
...  
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Epithelial Cells ◽  
Airway Inflammation ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Wild Type ◽  
Deficient Mice

Exposure to cigarette smoke (CS) is the main risk factor for developing chronic obstructive pulmonary disease and can induce airway epithelial cell damage, innate immune responses, and airway inflammation. We hypothesized that cell survival factors might decrease the sensitivity of airway epithelial cells to CS-induced damage, thereby protecting the airways against inflammation upon CS exposure. Here, we tested whether Pim survival kinases could protect from CS-induced inflammation. We determined expression of Pim kinases in lung tissue, airway inflammation, and levels of keratinocyte-derived cytokine (KC) and several damage-associated molecular patterns in bronchoalveolar lavage in mice exposed to CS or air. Human bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) in the presence or absence of Pim1 inhibitor and assessed for loss of mitochondrial membrane potential, induction of cell death, and release of heat shock protein 70 (HSP70). We observed increased expression of Pim1, but not of Pim2 and Pim3, in lung tissue after exposure to CS. Pim1-deficient mice displayed a strongly enhanced neutrophilic airway inflammation upon CS exposure compared with wild-type controls. Inhibition of Pim1 activity in BEAS-2B cells increased the loss of mitochondrial membrane potential and reduced cell viability upon CSE treatment, whereas release of HSP70 was enhanced. Interestingly, we observed release of S100A8 but not of double-strand DNA or HSP70 in Pim1-deficient mice compared with wild-type controls upon CS exposure. In conclusion, we show that expression of Pim1 protects against CS-induced cell death in vitro and neutrophilic airway inflammation in vivo. Our data suggest that the underlying mechanism involves CS-induced release of S100A8 and KC.

scholarly journals P. aeruginosa Induced Lipid Peroxidation Causes Ferroptotic Cell Death in Airways

2021 ◽  
Vol 55 (5) ◽  
pp. 590-604
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Phospholipid Scramblase ◽  
Human Airway ◽  
Cl Channel ◽  
Human Airway Epithelial Cells

BACKGROUND/AIMS: Oxidative stress and infections by Pseudomonas aeruginosa (P. aeruginosa) are prominent in lungs of patients suffering from cystic fibrosis (CF). METHODS: The present study examines effects of P. aeruginosa on lipid peroxidation in human and mouse lungs, and cell death induced by P. aeruginosa in human airway epithelial cells. The role of the Ca2+ activated Cl- channel TMEM16A, the phospholipid scramblase TMEM16F, and the CFTR Cl- channel for ferroptotic cell death is examined. RESULTS: Lipid peroxidation was detected in human CF lungs, which correlated with bacterial infection. In vivo inoculation with P. aeruginosa or Staphylococcus aureus (S. aureus) induced lipid peroxidation in lungs of mice lacking expression of CFTR, and in lungs of wild type animals. Incubation of CFBE human airway epithelial cells with P. aeruginosa induced an increase in reactive oxygen species (ROS), causing lipid peroxidation and cell death independent of expression of wt-CFTR or F508del-CFTR. Knockdown of TMEM16A attenuated P. aeruginosa induced cell death. Antioxidants such as coenzyme Q10 and idebenone as well as the inhibitor of ferroptosis, ferrostatin-1, inhibited P. aeruginosa-induced cell death. CFBE cells expressing wtCFTR, but not F508del-CFTR, activated a basal Cl- conductance upon exposure to P. aeruginosa, which was caused by an increase in intracellular basal Ca2+ concentrations and activation of Ca2+-dependent adenylate cyclase. CONCLUSION: The data suggest an intrinsic pro-inflammatory phenotype in CF epithelial cells, while ferroptosis is observed in both non-CF and CF epithelial cells upon infection with P. aeruginosa. CF cells fail to activate fluid secretion in response to infection with P. aeruginosa. The use of antioxidants and inhibitors of ferroptosis is proposed as a treatment of pneumonia caused by infection with P. aeruginosa.

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