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In vitro NHBE model of the human bronchial epithelium for toxicological testing

Prytherch, Zoe 2010. In vitro NHBE model of the human bronchial epithelium for toxicological testing. PhD Thesis, Cardiff University.

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Abstract

The respiratory tract is the primary site of exposure to inhaled substances. A growing need exists for high throughput in vitro models of the respiratory epithelium, which can provide rapid, reliable safety and effective screening in preclinical drug development applications. Normal human bronchial epithelial (NHBE) cells were cultured at an air-liquid interface in order to produce an in vitro model of the respiratory epithelium for toxicological testing. Extensive biochemical and morphological characterisation during construct development revealed that the NHBE model formed a pseudo-stratified, fully-differentiated culture of muco-ciliary phenotype. Histochemical and immunohistochemical techniques allowed the identification of basal, Clara, goblet and ciliated cells. Developmental characterisation revealed a toxicological dosing window of 7 days, where the model was deemed to be fully-established. Fully-developed NHBE cultures were then exposed to classical pulmonary toxicants (CPT) Lipopolysaccharide, cadmium chloride, paraquat, Amiodarone and cigarette smoke. Conventional toxicology techniques (culture viability, trans-epithelial electrical resistance TEER and morphology) were utilised to monitor the NHBE response to each CPT. The NHBE model responded with both general and toxicant-specific defence/irritancy mechanisms, observed to take place in the human bronchial epithelium and as such, reflective of in vivo toxicity. The in vitro model was finally challenged with candidate respiratory drugs (AstraZeneca AZ ) to test the utility of the cell system as a drug pre-screening tool. Blind-exposure of AZ compounds were characterised (physicochemical/ biochemically/morphologically) in the in vitro model and compared to AZ in vivo (rat) parallel exposure, focusing on irritancy end-points. A comparison of in vitro to in vivo exposures resulted in a 76.9 - 85% correlation of irritancy responses.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QR Microbiology > QR355 Virology
ISBN: 9781303218118
Funders: AstraZeneca
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 05:56
URI: http://orca-mwe.cf.ac.uk/id/eprint/54972

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