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Endocrine Abstracts (2014) 34 P375 | DOI: 10.1530/endoabs.34.P375

SFEBES2014 Poster Presentations Steroids (39 abstracts)

Increased lipopolysaccharide-induced neutrophilia in mice lacking the glucocorticoid receptor in bronchial epithelial (Clara) cells

Louise Kearney 1 , Julie Gibbs 2 , Stuart Farrow 3 , David Ray 2 & Andrew Loudon 1


1Faculty of Life Sciences, University of Manchester, Manchester, UK; 2Faculty of Medical and Human Sciences, Institute of Human Development, University of Manchester, Manchester, UK; 3Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline plc, Stevenage, UK.


One in five people in the UK is affected by lung disease, along with millions more worldwide. Glucocorticoids represent the most utilized anti-inflammatory therapy for the treatment of pulmonary inflammation, however a subset of patients exist which do not respond to therapeutically relevant doses.

The non-ciliated bronchial epithelial (Clara) cells have been identified as key mediators of the pulmonary inflammatory response. The glucocorticoid receptor (GR) is expressed ubiquitously throughout the lung, including within the Clara cells. To test whether the effectiveness of glucocorticoid therapy is linked to signalling through these cells we bred the GRflox mouse (Schütz lab, DKFZ, via the European Mutant Mouse Archive) with CCSPicre mice (DeMayo lab, Baylor College of Medicine, Texas) to generate a novel transgenic mouse line with targeted deletion of GR in the Clara cell.

Aerosolised bacterial endotoxin (lipopolysaccharide, LPS) was utilised as a tissue-specific stimulus to provoke a localised neutrophilic inflammatory response within the lung. Mice lacking GR in Clara cells (GRflox, CCSPicre+ve) exhibit a two fold increase in neutrophil recruitment to the lung compared to CCSPicre–ve littermates. However, in line with the control littermates, this neutrophil infiltration is ameliorated by pre-treatment with intraperitoneal injection of dexamethasone (1 mg/kg).

These results illustrate the importance of the Clara cell GR in mediating the anti-inflammatory effects of endogenous glucocorticoids, but also implicate additional GR expressing cell types within the lung in modulating dexamethasone-induced repression of the pulmonary inflammatory response.

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