Lovastatin induces fibroblast apoptosis in vitro and in vivo. A possible therapy for fibroproliferative disorders.
Diseases associated with pathological fibroproliferation represent a major cause of morbidity and mortality. Despite the importance of this class of disorders, current therapy is of limited value, and no therapy is available to reduce the fibroblast population size within existing fibrotic lesions. In this regard, constitutive expression of growth-promoting genes can sensitize cells to undergo apoptosis. Studies in our laboratory have demonstrated that lovastatin potently induces apoptosis in fibroblasts constitutively expressing Myc, and that lung fibroblasts isolated from fibrotic lesions constitutively express growth-promoting genes. In this study, we sought to determine if nontransformed lung fibroblasts would manifest susceptibility to lovastatin-induced apoptosis similar to that observed in fibroblasts ectopically expressing Myc. Here we show that clinically achievable concentrations of lovastatin induce apoptosis in normal and fibrotic lung fibroblasts in vitro, as evidenced by acridine orange staining, terminal transferase nick end translation (TUNEL), and DNA laddering. Apoptosis of human lung fibroblasts was dose- and time-dependent, and blocked by exogenous mevalonic acid. Furthermore, apoptosis was associated with decreased levels of mature Ras, a molecule directly implicated in fibroblast rescue from apoptosis. The ability of lovastatin to induce fibroblast apoptosis in vivo was examined using a guinea pig wound chamber model. Lovastatin (5 microM, 8 d) reduced granulation tissue formation in the wound chambers by 64.7%, with associated ultrastructural evidence of fibroblast apoptosis. These findings support further study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors as potential therapy for patients with fibroproliferative disorders.
Tan
A
A
Department of Medicine, Pulmonary, Allergy and Critical Care Division, and Department of Internal Medicine, University of Minnesota Medical School, Minneapolis, USA.
Levrey
H
H
Dahm
C
C
Polunovsky
V A
VA
Rubins
J
J
Bitterman
P B
PB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005355:Fibrosis; D006097:Granulation Tissue / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D008148:Lovastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D008798:Mevalonic Acid / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000628:therapy; D012016:Reference Values; D014945:Wound Healing / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D008148:Lovastatin; D018631:ras Proteins; D008798:Mevalonic Acid