Inhibition of key cytokines by tetrathiomolybdate in the bleomycin model of pulmonary fibrosis

Tetrathiomolybdate is an anticopper drug with a unique mechanism of action. Tetrathiornolybdate complexes copper to protein and itself, rendering the copper unavailable for cellular uptake. It was originally developed for Wilson's disease, and is now being developed as an antiangiogenic agent for the treatment of cancer. Many angiogenic cytokines require normal levels of copper, and lowered copper levels reduce cytokine signaling while cellular copper requirements are met. Cytokines of fibrosis and inflammation may be similarly copper dependent, since tetrathiomolybdate inhibits bleomycin induced pulmonary inflammation and fibrosis. The basis for this inhibition was evaluated here by examination of tetrathiomolybdate effects on cytokines in lung pathophysiologically important in the bleomycin mouse model of pulmonary damage. Results in mice injected enclotracheally with bleomycin confirmed that tetrathiomolybdate therapy was effective in reducing fibrosis. This effect was associated with significant inhibition of bleomycininduced tumor necrosis factor alpha and transforming growth factor beta expression in lung homogenates. These effects were shown to be independent of one another. This indicates that tetrathiomolybdate therapy can be effective even when fibrosis is at a more chronic stage, wherein inflammatory cytokines are playing a diminishing role. The inhibition of tumor necrosis factor alpha suggests that diseases of tumor necrosis factor alpha overexpression are also potential targets of tetrathiornolybdate therapy. (C) 2004 Elsevier Inc. All rights reserved.