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1 North West Lung Research Centre, 3 Dept of Pathology, South Manchester University NHS Hospitals Trust, Wythenshawe Hospital, Manchester and 2 Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, Royal Free and University College Medical School, Rayne Institute, London, UK
CORRESPONDENCE: J.J. Egan, Mater Misericordiae Hospital, Eccles Street, Dublin 7, Ireland. Fax: 35 318858280. E-mail: jegan@mater.ie
Keywords: bleomycin, collagen, idiopathic pulmonary fibrosis, RAD, rapamycin
Received: September 19, 2001
Accepted January 11, 2002
The present study was supported by the Medical Research Council (UK), the Wellcome Trust (programme grant no. 051154) and the Middlesex Hospital Special Trustees.
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease.
In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg·kg–1·day–1) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline.
In animals given bleomycin and drug vehicle, total lung collagen was increased by 182±11% (mean±sem) compared with saline controls at 14 days (p<0.001). The increase in lung-collagen accumulation was reduced by 75±12% (p<0.01) in animals given SDZ RAD and was accompanied by a concomitant 56±6% (p<0.001) reduction in lung weight.
SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.
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