Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice.
Tetrathiomolybdate (TM), a drug developed for the treatment of Wilson's disease, produces an antiangiogenic effect by reducing systemic copper levels. Several angiogenic cytokines appear to depend on normal levels of copper for activity. In both animal tumor models and in cancer patients, TM therapy has proved effective in inhibiting the growth of tumors. We have hypothesized that the activities of fibrotic and inflammatory cytokines are also subject to modulation by the availability of copper in a manner similar to angiogenic cytokines. As a first step in evaluating whether TM plays a therapeutic role in diseases of inflammation and fibrosis, we studied the effects of TM on a murine model of bleomycin-induced pulmonary fibrosis. Oral TM therapy resulted in dose-dependent reduction in serum ceruloplasmin, a surrogate marker of systemic copper levels. Significant decreases in systemic copper levels were associated with marked reduction in lung fibrosis as determined on the basis of histopathologic findings and a biochemical measure of fibrosis. The protection afforded by TM was also reflected in significantly reduced bleomycin-induced body-weight loss. In the next phase of this work, we will seek to determine the mechanisms by which TM brings about this therapeutic benefit.
Brewer
George J
GJ
Department of Human Genetics, University of Michigan Medical School, Ann Arbor 48109-0618, USA. brewergj@umich.edu
Ullenbruch
Matthew R
MR
Dick
Robert
R
Olivarez
Leovigildo
L
Phan
Sem H
SH
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D002570:Ceruloplasmin / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D008982:Molybdenum / Q000008:administration & dosage / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
D020533:Angiogenesis Inhibitors; D001761:Bleomycin; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin; D006909:Hydroxyproline