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 d isorders, 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 sensi tize cells to undergo apoptosis. Studies in our laboratory have demonstrate d that lovastatin potently induces apoptosis in fibroblasts constitutively expressing Myc, and that lung fibroblasts isolated from fibrotic lesions co nstitutively express growth-promoting genes. In this study, we sought to de termine if nontransformed lung fibroblasts would manifest susceptibility to lovastatin-induced apoptosis similar to that observed in fibroblasts ectop ically expressing Myc. Here we show that clinically achievable concentratio ns of lovastatin induce apoptosis in normal and fibrotic lung fibroblasts i n vitro, as evidenced by acridine orange staining, terminal transferase nic k end translation (TUNEL), and DNA laddering. Apoptosis of human lung fibro blasts was dose- and time-dependent, and blocked by exogenous mevalonic aci d. Furthermore, apoptosis was associated with decreased levels of mature Ra s, a molecule directly implicated in fibroblast rescue from apoptosis. The ability of lovastatin to induce fibroblast apoptosis in vivo was examined u sing a guinea pig wound chamber model. Lovastatin (5 mu M, 8 d) reduced gra nulation tissue formation in the wound chambers by 64.7%, with associated u ltrastructural evidence of fibroblast apoptosis. These findings support fur ther study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inh ibitors as potential therapy for patients with fibroproliferative disorders .