Apoptosis and the Airway Epithelium

White, Steven R.

doi:10.1155/2011/948406

Cited by 39 publications

(46 citation statements)

References 236 publications

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“…Consistently, a previous study reported NET‐induced apoptosis of A549 cells . The survival of AECs requires adhesion to basement membranes; consequently, cell detachment is followed by cell death . In the present study, NETs down‐regulated the expression of epithelial TJ proteins, occludin and claudin‐1, which could be a mechanism of NET‐induced AEC detachment followed by cell death.…”

Section: Discussionsupporting

confidence: 91%

Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma

Pham

Ban

Kim

et al. 2016

Clin Experimental Allergy

150

126

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SummaryBackground Autophagy and neutrophil extracellular DNA traps (NETs) are implicated in asthma; however, their roles in asthma pathogenesis have not been elucidated. Objectives We compared autophagy and NET production levels from peripheral blood neutrophils (PBNs) of patients with severe asthma (SA) and non-severe asthma (NSA). Additionally, we investigated the inflammatory effects of NETs on human airway epithelial cells (AECs) and peripheral blood eosinophils (PBEs). Methods Peripheral blood neutrophils from patients with SA (n = 30) and NSA (n = 38) were treated with interleukin (IL)-8 (100 ng/mL). Autophagy (light chain 3-II expression) and NET production levels were evaluated by Western blot, immunofluorescence microscopy, and PicoGreen assay. The effects of NETs on AECs were assessed by investigating cell death, cell detachment, expression of occludin and claudin-1, and IL-8 production; the effects of NETs on PBEs were examined by investigating the activation and release of eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN). Results Untreated and IL-8-treated PBNs from the SA group produced higher autophagy and NET levels compared with those from the NSA group (P < 0.01). IL-8 increased autophagy and NET levels in PBNs from the SA group, but not from the NSA group. NET levels were correlated with autophagy levels in PBNs (P < 0.001). IL-8-induced NET production levels negatively were correlated with FEV1/FVC (r = À0.700, P = 0.016). NETs induced cell death, detachment, degradation of occludin and claudin-1, and IL-8 production from AECs. Higher levels of NET-induced ECP and EDN were released from PBEs in SA compared with NSA groups. Conclusions and Clinical Relevance Neutrophil autophagy and NETs could enhance asthma severity by damaging airway epithelium and triggering inflammatory responses of AECs and PBEs. Modulating neutrophil autophagy and NET production may be a new target therapy for SA.

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Section: Discussionsupporting

confidence: 91%

Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma

Pham

Ban

Kim

et al. 2016

Clin Experimental Allergy

150

126

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“…Exposure to environmental pollutants, allergens and pathogens can induce apoptosis of airway epithelial cells 3,6,4,7 . In fact, clusters of uncleared epithelial cells referred to as ‘Creola bodies’ in the sputum have been seen in patients with asthma for decades 8,9 .…”

mentioning

confidence: 99%

Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation

Juncadella

Kadl

Sharma

et al. 2012

Nature

261

236

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Lung epithelial cells can influence immune responses to airway allergens1,2. Airway epithelial cells also undergo apoptosis after encountering environmental allergens3; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells1,4,5. Administration of exogenous IL-10 ‘rescued’ the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.

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“…; Basinski et al. ), we were unable to elicit apoptosis exclusively through exposure to TNFα and IFNγ, a situation which may reflect differences in cell culture (White ). For example, unlike AECs cultured directly from donors, the commonly used normal human bronchial epithelial (NHBE) cell line can grow on a plastic substratum, and are often examined at subconfluence.…”

Section: Discussionmentioning

confidence: 78%

“…; Makinde et al. ; White ). However, apoptosis of AECs in asthmatics has been observed in the absence of prolonged inflammation, and demonstrate abnormalities for the production of Bcl2 and activation of caspases (Cohen et al.…”

Section: Introductionmentioning

confidence: 99%

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Cellular inhibitor of apoptosis-2 is a critical regulator of apoptosis in airway epithelial cells treated with asthma-related inflammatory cytokines

et al. 2013

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Aberrant apoptosis of airway epithelial cells (AECs) is a disease contributing feature in the airways of asthmatics. The proinflammatory cytokines tumor necrosis factor α (TNFα) and interferon γ (IFNγ) are increased in asthma and have been shown to contribute to apoptosis at the airways. In the present study, we investigated the role of the inhibitor of apoptosis protein (IAP) family in primary AECs exposed to TNFα and IFNγ. IAPs are potent regulators of caspase activity elicited by the intrinsic and extrinsic apoptosis pathways. However, while caspase-mediated apoptosis was observed in AECs exposed to doxorubicin, it was not observed after cytokine treatment. Instead, AECs exhibited proapoptotic changes evidenced by an increased Bax:Bcl2 transcript ratio and partial processing of procaspase-3. Examination by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western analysis showed that proapoptotic changes were associated with a time- and dose-dependent induction of cellular IAP-2 (cIAP2), potentiated primarily by IFNγ. The abundance of the IAP antagonists X-linked IAP-associated factor 1 (XAF1) and second mitochondria-derived activator of caspases did not change, although a moderate nuclear redistribution was observed for XAF1, which was also observed for cIAP2. Small interfering RNA (siRNA)-mediated depletion of cIAP2 from AECs leads to caspase-3 activation and poly (ADP-ribose) polymerase cleavage, but this required extended cytokine exposure to produce a concomitant decrease in cIAP1 and Bcl2. These results indicate that AECs possess endogenous mechanisms making them highly resistant to apoptosis due to asthma-related inflammatory cytokines, and the activity of cIAP2 plays an important role in this protection.

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Apoptosis and the Airway Epithelium

Cited by 39 publications

References 236 publications

Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma

Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma

Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation

Cellular inhibitor of apoptosis-2 is a critical regulator of apoptosis in airway epithelial cells treated with asthma-related inflammatory cytokines

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