PURPOSE: Transforming growth factor-beta1 (TGF-beta1) has been known to be involved in the pathogenesis of Peyronie's disease (PD). In the present study, we investigated the therapeutic effect of IN-1130, a novel small molecule inhibitor of activin receptor-like kinase (ALK)5, a type I receptor of TGF-beta, in an animal model of PD induced by fibrin. MATERIALS AND METHODS: Four-month-old male Sprague-Dawley rats were divided into three groups (n=4 per group): group 1, age-matched control; group 2, PD rats without treatment; group 3, PD rats receiving an intratunical injection of IN-1130 (on day 20, 5 mg/kg in 0.1 ml saline) into the lesion. PD was induced in rats through repeated injections of fibrin (50 microliter each of human fibrin and thrombin solutions, days 0, 3, and 6, respectively) into the tunica albuginea. Penile curvature was evaluated by use of an artificialerection test on day 30. The penis was then harvested and stained with Masson trichrome, hematoxylin- eosin, and antibody to vimentin and phospho-Smad2. RESULTS: PD rats receiving repeated intratunical injections of fibrin revealed an infiltration of inflammatory cells, including lymphocytes, plasma cells, and fibroblasts, and an increase in transnuclear expression of phospho-Smad2 in the fibrotic plaque. However, repeated intratunical injections of fibrin did not induce penile curvature. IN-1130 induced significant regression of fibrotic plaque through reduced infiltration of inflammatory cells and reduced transnuclear expression of phospho-Smad2. CONCLUSIONS: Inhibition of TGF-beta pathway through the use of ALK5 inhibitors may be a curative local treatment modality for PD.
Activin Receptors ; Animals ; Eosine Yellowish-(YS) ; Fibrin ; Fibroblasts ; Humans ; Imidazoles ; Lymphocytes ; Male ; Models, Animal ; Penile Induration ; Penis ; Phosphotransferases ; Plasma Cells ; Quinoxalines ; Rats ; Rats, Sprague-Dawley ; Thrombin ; Transforming Growth Factor beta ; Vimentin