Pentoxifylline attenuates transforming growth factor-beta1-stimulated elastogenesis in human tunica albuginea-derived fibroblasts part 2: Interference in a TGF-beta1/Smad-dependent mechanism and downregulation of AAT1.

INTRODUCTION: Transforming growth factor-beta1 (TGF-beta1) contributes to the pathogenesis of Peyronie's disease (PD). Pentoxifylline (PTX) antagonizes the effects of TGF-beta1 and has been utilized in our clinic for the management of PD although the mechanisms of action are not entirely clear. AIM: We studied cell-signaling pathways through which TGF-beta1 and PTX mediate collagen metabolism, elastin expression, and elastogenesis in tunica albuginea-derived fibroblasts (TADFs). METHODS: TADFs from men with and without PD were cultured and treated with TGF-beta1 and PTX as monotherapy at differing concentrations and time points. Combination treatment (TGF-beta1 followed by PTX and vice versa) was also investigated. MAIN OUTCOME MEASURES: Reverse-transcription polymerase chain reaction and Western blotting were utilized to assess differences in elastin metabolism and cellular signaling between groups. Alpha-1 antitrypin (AAT1) expression was assayed. RESULTS: At doses greater than 0.1 ng/Ml, TGF-beta1 increased messenger ribonucleic acid (mRNA) and protein expression of elastin in a time-dependent fashion in TADF. PTX did not interfere with TGF-beta1 mediated upregulation of elastin mRNA and protein in TADF. However, pretreatment of TADF with PTX was associated with decreased expression of AAT1, decreased activity of the Smad1/5 pathway, and enhanced phosphorylation of the inhibitory Smad6. CONCLUSION: Expression of elastin mRNA and protein is upregulated in TADF by TGF-beta1. PTX has no effect on elastin production but attenuates elastogenesis in TADF through an AAT1-related mechanism.