Recent advances in human respiratory epithelium models for drug discovery

Yaqub, Naheem; Wayne, Gareth; Birchall, Martin A.; Song, Wenhui

doi:10.1016/j.biotechadv.2021.107832

Cited by 33 publications

(19 citation statements)

References 307 publications

(393 reference statements)

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“…Indeed, EVLP is a relatively recent procedure that has proved to (1) increase lung parenchyma recruitment, (2) reduce lung edema incidence and severity and improve graft gas exchange performance, thanks to the hyperoncotic solution perfusion, and (3) allow to implement specific treatments (e.g., antibiotics), ultimately increasing the donor graft pool. 10,15,[18][19][20][22][23][24][25][26][27] Clinical trial results further supported its adoption by showing equal outcomes of EVLP-treated grafts compared with the conventional approach. 14,[28][29][30][31][32][33] However, some aspects of EVLP are still debated, such as the best protocol to be used, the limits and consequences of graft manipulation, and the effect on bronchial ischemia and anastomotic complications.…”

Section: Discussionmentioning

confidence: 92%

“…[38][39][40] In the EVLP setting, this approach still needs to be thoroughly explored, but we believe that our data could represent a significant starting point. 22,[25][26][27] Our study presents a few limitations: the digestion and cell isolation process could have affected cell viability, although it would have equally affected both types of graft. Moreover, this event was not observed in our previous study using the same protocol, although performed in a different context.…”

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Is there life on the airway tree? A pilot study of bronchial cell vitality and tissue morphology in the ex vivo lung perfusion (EVLP) era of lung transplantation

et al. 2022

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Background: Ex vivo lung perfusion (EVLP) is a relevant procedure to increase the lung donor pool but could potentially increase the airway tree ischemic injury risk.Methods: This study aimed to evaluate the direct effect of EVLP on the airway tree by evaluating bronchial cell vitality and tissue signs of injury on a series of 117 bronchial rings collected from 40 conventional and 19 EVLP-treated lung grafts. Bronchial rings and related scraped bronchial epithelial cells were collected before the EVLP procedure and surgical anastomosis. Results:The preimplantation interval was significantly increased in the EVLP graft group (p < 0.01). Conventional grafts presented cell viability percentages of 47.07 ± 23.41 and 49.65 ± 21.25 in the first and second grafts which did not differ significantly from the EVLP group (first graft 50.54 ± 25.83 and second graft 50.22 ± 20.90 cell viability percentage). No significant differences in terms of histopathological features (edema, inflammatory infiltrate, and mucosa ulceration) were observed comparing conventional and EVLP samples. A comparison of bronchial cell viability and histopathology of EVLP samples retrieved at different time intervals revealed no significant differences. Accordingly, major bronchial complications after lung transplant were not observed in both groups.Conclusions: Based on these data, we observed that EVLP did not significantly impact bronchial cell vitality and airway tissue preservation nor interfere with bronchial anastomosis healing, further supporting it as a safe and useful procedure.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Is there life on the airway tree? A pilot study of bronchial cell vitality and tissue morphology in the ex vivo lung perfusion (EVLP) era of lung transplantation

et al. 2022

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“…The pathogenesis of ALI has not been clearly elucidated. Currently, its clinical treatment mainly includes protective mechanical ventilation, with no effective drug for its treatment [ 5 , 6 ]. Therefore, it is important to elucidate the detailed pathogenesis and pathophysiological mechanisms of ALI and develop effective drugs for its treatment.…”

Section: Introductionmentioning

confidence: 99%

Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses

Deng

et al. 2022

Cell Mol Biol Lett

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Background Acute lung injury (ALI) has received considerable attention in the field of intensive care as it is associated with a high mortality rate. Obacunone (OB), widely found in citrus fruits, is a natural bioactive compound with anti-inflammatory and antioxidant activities. However, it is not clear whether OB protects against lipopolysaccharide (LPS)-induced ALI. Therefore, in this study, we aimed to evaluate the protective effects of OB and the potential mechanisms against LPS-induced ALI and BEAS-2B cell injury. Methods We established a model of BEAS-2B cell injury and a mouse model of ALI by treating with LPS. Samples of in vitro model were subjected to cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release assays. The total number of cells and neutrophils, protein content, and levels of IL-6, TNF-α, and IL-1β were determined in bronchoalveolar lavage fluid (BALF). Glutathione, reactive oxygen species, and malondialdehyde levels were determined in lung tissue. Additionally, immunohistochemical analysis, immunofluorescence, western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay were conducted to examine the effects of OB. Furthermore, mice were treated with an Nrf2 inhibitor (ML385) to verify its role in ferroptosis. Data were analyzed using one-way analysis of variance or paired t-tests. Results Compared with the LPS group, OB effectively alleviated LPS-induced ALI by decreasing lung wet/dry weight ratio, reactive oxygen species and malondialdehyde production, and superoxide dismutase and glutathione consumption in vivo. In addition, OB significantly alleviated lung histopathological injury, reduced inflammatory cytokine secretion and Fe2+ and 4-HNE levels, and upregulated GPX4, SLC7A11, and Nrf2 expression. Mechanistically, OB activated Nrf2 by inhibiting Nrf2 ubiquitinated proteasome degradation. ML385 reversed the protective effects of OB against LPS-induced ALI. Conclusion Overall, OB alleviates LPS-induced ALI, making it a potential novel protective agent against LPS-induced ALI.

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“…Therefore, Rho GTPases, and Cdc42 in particular, are interesting candidates in the regulation of cytokine and chemokine upregulation and secretion in bronchial epithelial cells. BEAS-2B cells are an immortalized human bronchial epithelial cell line that has been widely used as an in vitro cell model for studies related to respiratory disease (14). In this study, we induced a state of inflammation in BEAS-2B cells through the treatment with different allergens and stimulants such as cockroach extract, polyinosinicpolycytidylic acid (poly(I:C)), and TNF-α.…”

Section: Introductionmentioning

confidence: 99%

Cdc42 regulates cytokine expression and trafficking in bronchial epithelial cells

Shouib

Eitzen

2022

Preprint

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Airway epithelial cells can respond to incoming pathogens, allergens and stimulants through the secretion of cytokines and chemokines. These pro-inflammatory mediators activate inflammatory signaling cascades that allow a robust immune response to be mounted. However, uncontrolled production and release of cytokines and chemokines can result in chronic inflammation and appears to be an underlying mechanism for the pathogenesis of pulmonary disorders such as asthma and COPD. The Rho GTPase, Cdc42, is an important signaling molecule that we hypothesize can regulate cytokine production and release from epithelial cells. We treated BEAS-2B lung epithelial cells with a set of stimulants to activate inflammatory pathways and cytokine release. The production, trafficking and secretion of cytokines were assessed when Cdc42 was pharmacologically inhibited with ML141 drug or silenced with lentiviral-mediated shRNA knockdown. We found that Cdc42 inhibition with ML141 differentially affected gene expression of a subset of cytokines; transcription of IL-6 and IL-8 were increased while MCP-1 was decreased. However, Cdc42 inhibition or depletion disrupted IL-8 trafficking and reduced its secretion even though transcription was increased. Cytokines transiting through the Golgi were particularly affected by Cdc42 disruption. Our results define a role for Cdc42 in the regulation of cytokine production and release in airway epithelial cells. This underscores the role of Cdc42 in coupling receptor activation to downstream gene expression and also as a regulator of cytokine secretory pathways.

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Recent advances in human respiratory epithelium models for drug discovery

Cited by 33 publications

References 307 publications

Is there life on the airway tree? A pilot study of bronchial cell vitality and tissue morphology in the ex vivo lung perfusion (EVLP) era of lung transplantation

Is there life on the airway tree? A pilot study of bronchial cell vitality and tissue morphology in the ex vivo lung perfusion (EVLP) era of lung transplantation

Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses

Cdc42 regulates cytokine expression and trafficking in bronchial epithelial cells

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