Role of Endoplasmic Reticulum Stress in Cystic Fibrosis-Related Airway Inflammatory Responses

Ribeiro, Carla M. P.; Boucher, Richard C.

doi:10.1513/pats.201001-017aw

Cited by 67 publications

(53 citation statements)

References 83 publications

(121 reference statements)

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“…Chronic airway inflammation is a hallmark in CF patients (Ribeiro & Boucher, 2010). Our study demonstrates that cytokines are still expressed at high levels in fully differentiated CF cell cultures, despite of dislodging the epithelial cells from the original organ and the following processes of dedifferentiation, proliferation and re-differentiation of a new epithelium, all in the absence of bacteria.…”

Section: Discussionmentioning

confidence: 65%

Acute toxicity of silver and carbon nanoaerosols to normal and cystic fibrosis human bronchial epithelial cells

et al. 2015

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Inhalation of engineered nanoparticles (NP) poses a still unknown risk. Individuals with chronic lung diseases are expected to be more vulnerable to adverse effects of NP than normal subjects, due to altered respiratory structures and functions. Realistic and dose-controlled aerosol exposures were performed using the deposition chamber NACIVT. Well-differentiated normal and cystic fibrosis (CF) human bronchial epithelia (HBE) with established air-liquid interface and the human bronchial epithelial cell line BEAS-2B were exposed to spark-generated silver and carbon nanoaerosols (20 nm diameter) at three different doses. Necrotic and apoptotic cell death, pro-inflammatory response, epithelial function and morphology were assessed within 24 h after aerosol exposure. NP exposure resulted in significantly higher necrosis in CF than normal HBE and BEAS-2B cells. Before and after NP treatment, CF HBE had higher caspase-3 activity and secreted more IL-6 and MCP-1 than normal HBE. Differentiated HBE had higher baseline secretion of IL-8 and less caspase-3 activity and MCP-1 secretion compared to BEAS-2B cells. These biomarkers increased moderately in response to NP exposure, except for MCP-1, which was reduced in HBE after AgNP treatment. No functional and structural alterations of the epithelia were observed in response to NP exposure. Significant differences between cell models suggest that more than one and fully differentiated HBE should be used in future toxicity studies of NP in vitro. Our findings support epidemiologic evidence that subjects with chronic airway diseases are more vulnerable to adverse effects of particulate air pollution. Thus, this sub-population needs to be included in nano-toxicity studies.

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Section: Discussionmentioning

confidence: 65%

Acute toxicity of silver and carbon nanoaerosols to normal and cystic fibrosis human bronchial epithelial cells

et al. 2015

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“…Since activation of XBP-1 mRNA splicing has a fundamental role in secretory responses in many cells, 33–37 including airway epithelia, 3–5,38 we evaluated whether IL-13-induced mucin production coupled to XBP-1 mRNA splicing in Calu-3 cultures. The same samples utilized in the studies described in Figure 7a were used in these studies.…”

Section: Resultsmentioning

confidence: 99%

The ER stress transducer IRE1β is required for airway epithelial mucin production

et al. 2013

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Inflammation of human bronchial epithelia (HBE) activates the endoplasmic reticulum (ER) stress transducer inositolrequiring enzyme 1 (IRE1)α, resulting in IRE1α-mediated cytokine production. Previous studies demonstrated ubiquitous expression of IRE1α and gut-restricted expression of IRE1β.We found that IRE1β is also expressed in HBE, is absent in human alveolar cells, and is upregulated in cystic fibrosis and asthmatic HBE. Studies with Ire1β−/− mice and Calu-3 airway epithelia exhibiting IRE1β knockdown or overexpression revealed that IRE1β is expressed in airway mucous cells, is functionally required for airway mucin production, and this function is specific for IRE1β vs. IRE1α. IRE1β-dependent mucin production is mediated, at least in part, by activation of the transcription factor X-box binding protein-1 (XBP-1) and the resulting XBP-1-dependent transcription of anterior gradient homolog 2, a gene implicated in airway and intestinal epithelial mucin production. These novel findings suggest that IRE1β is a potential mucous cell-specific therapeutic target for airway diseases characterized by mucin overproduction.

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“…Three general mechanisms have evolved to restore ER homeostasis-increase in the protein folding capacity, attenuation of translation, and upregulation of the degradation machinery (ER-associated degradation, autophagy) (43). It is important to appreciate that in addition to misfolding of mutated CFTR protein, many factors are likely to have an impact on proteostasis to trigger ER stress in CF, including oxidative stress (11,16,17,(44)(45)(46), chronic infection (47), and decreased functionality of ER stress relief mechanisms, such as autophagy (21).…”

Section: Discussionmentioning

confidence: 99%

Atypical Activation of the Unfolded Protein Response in Cystic Fibrosis Airway Cells Contributes to p38 MAPK-Mediated Innate Immune Responses

Blohmke

Mayer

Tang

et al. 2012

The Journal of Immunology

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Inflammatory lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF); understanding what produces dysregulated innate immune responses in CF cells will be pivotal in guiding the development of novel anti-inflammatory therapies. To elucidate the molecular mechanisms that mediate exaggerated inflammation in CF following TLR signaling, we profiled global gene expression in immortalized human CF and non-CF airway cells at baseline and after microbial stimulation. Using complementary analysis methods, we observed a signature of increased stress levels in CF cells, specifically characterized by endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and MAPK signaling. Analysis of ER stress responses revealed an atypical induction of the UPR, characterized by the lack of induction of the PERK–eIF2α pathway in three complementary model systems: immortalized CF airway cells, fresh CF blood cells, and CF lung tissue. This atypical pattern of UPR activation was associated with the hyperinflammatory phenotype in CF cells, as deliberate induction of the PERK–eIF2α pathway with salubrinal attenuated the inflammatory response to both flagellin and Pseudomonas aeruginosa. IL-6 production triggered by ER stress and microbial stimulation were both dependent on p38 MAPK activity, suggesting a molecular link between both signaling events. These data indicate that atypical UPR activation fails to resolve the ER stress in CF and sensitizes the innate immune system to respond more vigorously to microbial challenge. Strategies to restore ER homeostasis and normalize the UPR activation profile may represent a novel therapeutic approach to minimize lung-damaging inflammation in CF.

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Role of Endoplasmic Reticulum Stress in Cystic Fibrosis-Related Airway Inflammatory Responses

Cited by 67 publications

References 83 publications

Acute toxicity of silver and carbon nanoaerosols to normal and cystic fibrosis human bronchial epithelial cells

Acute toxicity of silver and carbon nanoaerosols to normal and cystic fibrosis human bronchial epithelial cells

The ER stress transducer IRE1β is required for airway epithelial mucin production

Atypical Activation of the Unfolded Protein Response in Cystic Fibrosis Airway Cells Contributes to p38 MAPK-Mediated Innate Immune Responses

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