Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.664270
Title: Metalloproteinases in lymphangioleiomyomatosis
Author: Chang, William Y. C.
ISNI:       0000 0004 5362 4781
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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Abstract:
Matrix metalloproteinases (MMPs) have been implicated in the lung destruction seen in lymphangioleiomyomatosis (LAM) as elevated MMP levels have been detected in tissue, serum and urine from LAM patients but a causal link has not been established. It has also been hypothesised that inhibition of MMPs with the tetracycline antibiotic doxycycline may provide a potential treatment for LAM. Previously proposed mechanisms of actions of doxycycline were examined. In Eker rat derived ELT3 cells doxycycline at doses ~25 micrograms/ml inhibited cell proliferation and adhesion, possibly by a toxic effect. This was also seen in human angiomyolipoma-derived cells. There was no effect of doxycycline on MMP-2 expression or activity in vitro. In a xenograft model, doxycycline had no effect on tumour growth, final tumour weight, or tumour lysate MMP levels. The role of MMPs as potential biomarkers was also compared with vascular endothelial growth factor D (VEGF-D). Serum VEGF-D, Angiotensin coverting enzyme (ACE) and total matrix metalloproteinase 2 (MMP-2) levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls and the addition VEGF-D measurement to ERS criteria reduced the need for biopsy to confirm diagnosis. Finally, we performed a 2 year, randomised, double blind placebo controlled study of doxycycline in 23 patients with LAM and found no evidence that it prevented decline in lung function, or improved exercise tolerance of quality of life.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.664270  DOI: Not available
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