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TB R&D Weekly Update: Drugs Targeting MMP-1 May Reduce Lung Pathology Caused by TB

Paul Elkington, Takayuki Shiomi, Ronan Breen, Robert K. Nuttall, Cesar Augusto Ugarte-Gil, Naomi F. Walker, Luísa Saraiva, Bernadette Pedersen, Francesco Mauri, Marc Lipman, Dylan R. Edwards, Brian D. Robertson, Jeanine D’Armiento and Jon S. Friedland. MMP-1 drives immunopathology in human tuberculosis and transgenic mice. J Clin Invest. 2011 Apr 25. [Epub ahead of print]

On March 1, 2011, we reviewed an article by Elkington, et al., that sought to redefine TB immunopathology by taking in account lung destruction by proteases. This week, Elkington, et al., presents significant data to support the premise that M. tuberculosis infection drives proteolytic destruction of the lung matrix contributing to lung damage caused by TB and to the morbidity and mortality of TB.

The authors focused on a family of proteases called MMPs which are zinc-dependent and can degrade all components of the extracellular matrix of the lung. MMPs are inhibited by TIMPs (tissue inhibitor of metalloproteinases). The series of experiments utilized clinical samples, primary human monocytes, and transgenic mice. Key points from the article include:

  • After analyzing clinical samples for concentrations of all MMPs, TIMPs, and related cell surface proteins, MMP-1 emerged as the principal secreted collagenase upregulated in TB. MMP-3 was also upregulated but to a lesser extent. Control samples were from patients with respiratory systems but did not have a final diagnosis of TB.
  • Analyzing samples from TB/HIV co-infected patients, MMP-1 still had increased concentrations. In HIV-negative TB patients, those with more extensive lung disease had higher MMP-1 concentrations.
  • Experiments with human monocytes and UV killed M. tb. demonstrated that MMP-1 could be upregulated in the absence of live mycobacteria.
  • Ro32-3555, a drug partially developed by Roche and used in Phase III clinical trials for arthritis, was shown to completely inhibit MMP-1 activity in M. tb.-infected primary human macrophages.
  • Mice do not have the tissue destruction seen in human disease. Wild type mice had intact alveolar walls when infected with M. tb. ,whereas, mice expressing human MMP-1 showed destroyed alveolar walls at the sites of infection.

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