The use of human nasal in vitro cell systems during drug discovery and development

Dimova, Svetlana; Brewster, M.; Noppe, M.; Jorissen, Mark; Augustijns, Patrick

doi:10.1016/j.tiv.2004.07.003

Cited by 105 publications

(109 citation statements)

References 82 publications

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“…Originally, cells for culture were obtained with more traumatic methods, such as punch biopsy, which may cause pain and bleeding. Punch biopsy also has the disadvantage of requiring a longer time to establish cell culture compared with cells collected by brushing [7,13,14]. The technique does, however, have the advantage of a high yield of culture results.…”

Section: Discussionmentioning

confidence: 99%

Rapid diagnosis of primary ciliary dyskinesia: cell culture and soft computing analysis

et al. 2012

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Diagnosis of primary ciliary dyskinesia (PCD) sometimes requires repeated nasal brushing to exclude secondary ciliary alterations. Our aim was to evaluate whether the use of a new method of nasal epithelial cell culture can speed PCD diagnosis in doubtful cases and to identify which are the most informative parameters by means of a multilayer artificial neural network (ANN).A cross-sectional study was performed in patients with suspected PCD. All patients underwent nasal brushing for ciliary motion analysis, ultrastructural assessment and evaluation of ciliary function after ciliogenesis in culture by ANN.151 subjects were studied. A diagnostic suspension cell culture was obtained in 117 nasal brushings. A diagnosis of PCD was made in 36 subjects (29 of whom were children). In nine out of the 36 patients the diagnosis was made only after a second brushing, because of equivocal results of both tests at first examination. In each of these subjects diagnosis of PCD was confirmed by cell culture results.Cell culture in suspension evaluated by means of ANN allows the separation of PCD from secondary ciliary dyskinesia patients after only 5 days of culture and allows diagnosis to be reached in doubtful cases, thus avoiding the necessity of a second sample.

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Section: Discussionmentioning

confidence: 99%

Rapid diagnosis of primary ciliary dyskinesia: cell culture and soft computing analysis

et al. 2012

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“…There are many efforts to reconstruct the in vivo tissue complexity using in vitro culture systems. Traditional submerged cultures exhibit a flat, squamous-like morphology and lack ciliated, secretory, and basal cells (Dimova et al, 2005). Recently developed three dimensional (3-D) human cell culture systems have allowed a better representation of the in vivo characteristics of the human respiratory tissue where the in vivo-like structure and function can be preserved.…”

Section: R4f Smoke and Ths22 Aerosol Exposure And Endpoint Generationmentioning

confidence: 99%

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

Iskandar

Mathis

Martin

et al. 2017

ALTEX

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ratory animals -to reduce the number of animals, to refine the design of procedures such that pain and distress are minimized, and to replace animal models with alternative methods and lower organisms when possible (Doke and Dhawale, 2015). In this regard, the capability to preserve human respiratory cells in culture provides a tool not only to generate mechanistic data, but also to improve the predicted effects of exposure hazard through inhalation in humans. An emphasis on assessment studies using human-derived in vitro culture systems will reduce the problems that are inherent to interspecies translatability (Manuppello and Sullivan, 2015).In vitro toxicology approaches have evolved from focusing on the molecular changes within a cell to understanding the toxicity-related mechanisms (cell-cell interactions) in models IntroductionMechanistic investigation of the impact of exposure on the lower airway remains challenging because access to lung tissues is limited. Although biopsy samples can be obtained from patients/donors for mechanistic studies of exposure-induced injury, a biopsy procedure is invasive and there are related ethical concerns (Peppercorn, 2013). Alternatively, animal studies allow the collection of biological samples from various animal models of human diseases. However, biological responses can vary among animal species, and findings obtained from animal studies may not apply to humans. Alternatives to animal testing have been proposed to overcome these drawbacks, including the 3Rs strategy -reduction, refinement, and replacement of labo- Research SummaryIn vitro toxicology approaches have evolved from a focus on molecular changes within a cell to understanding of toxicity-related mechanisms in systems that can mimic the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offers a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus, the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. Aligned with 3Rs strategy, this study aimed to explore the relevance of a human 3-D nasal culture model to assess the toxicological impact of aerosols generated from a candidate modified risk tobacco product (cMRTP), the Tobacco Heating System (THS) 2.2, as compared with smoke generated from reference cigarette 3R4F. A series of experimental repetitions, where multiple concentrations of THS2.2 aerosol and 3R4F smoke were applied, were conducted to obtain reproducible measurements to understand the cellular/molecular changes that occur following exposure. In agreement with "Toxicity Testing in the 21 st Century -a Vision and a Strategy", this study implemented a systems toxicology approach and found that for all tested concentrations the impa...

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“…To test our hypotheses, we used primary human sinonasal cells genotyped for TAS2R38 (encoding T2R38) and cultured at an air-liquid interface (ALI), recapitulating the polarized respiratory epithelium. ALI cultures are a state-of-the-art epithelial model that has been used for extensive studies of the upper (36) and lower airways (37). We measured three indexes of respiratory innate defense, NO production, mucociliary clearance, and bactericidal activity.…”

Section: Introductionmentioning

confidence: 99%

T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection

Lee

Xiong²,

Kofonow³

et al. 2012

J. Clin. Invest.

500

1,003

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Innate and adaptive defense mechanisms protect the respiratory system from attack by microbes. Here, we present evidence that the bitter taste receptor T2R38 regulates the mucosal innate defense of the human upper airway. Utilizing immunofluorescent and live cell imaging techniques in polarized primary human sinonasal cells, we demonstrate that T2R38 is expressed in human upper respiratory epithelium and is activated in response to acyl-homoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram-negative bacteria. Receptor activation regulates calcium-dependent NO production, resulting in stimulation of mucociliary clearance and direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene were linked to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Lastly, TAS2R38 genotype correlated with human sinonasal gram-negative bacterial infection. These data suggest that T2R38 is an upper airway sentinel in innate defense and that genetic variation contributes to individual differences in susceptibility to respiratory infection.

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The use of human nasal in vitro cell systems during drug discovery and development

Cited by 105 publications

References 82 publications

Rapid diagnosis of primary ciliary dyskinesia: cell culture and soft computing analysis

Rapid diagnosis of primary ciliary dyskinesia: cell culture and soft computing analysis

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection

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