Pulmonary cavitation, a hallmark of tuberculosis (TB), is the site of high mycobacterial
burden leading to disease transmission. The cause of tissue destruction leading to cavitation
in TB is primarily due to the host inflammatory response. A matrix degrading phenotype
develops in TB, in which the activity of host proteolytic enzymes, specifically matrix
metalloproteinases (MMPs) is unopposed by their specific Tissue Inhibitors of
Metalloproteinases (TIMPs), thus driving tissue destruction and cavitation in TB. This tissue
destruction causes morbidity and mortality. MMP inhibition with doxycycline has shown to
improve lung function in patients with chronic lung diseases but its use in TB is unclear.
We hypothesise that the MMP inhibitor doxycycline will reduce tissue destruction in human
pulmonary tuberculosis.
Specific aims:
- To investigate the MMP and TIMP secretion and gene expression in M. tuberculosis (M.tb)
- infected primary neutrophils and monocytes from healthy volunteers taking doxycycline.
- To investigate the intracellular signaling pathways modulated by doxycycline
- To investigate the effects doxycycline has on biological markers of tissue destruction
in TB patients
- To assess the tolerability and side effects of doxycycline with concurrent standard TB
therapy
Phase:
Phase 2
Details
Lead Sponsor:
National University Hospital, Singapore
Collaborators:
A*Star National University, Singapore Tan Tock Seng Hospital