Get access

Pentoxifylline Attenuates Transforming Growth Factor-β1-Stimulated Elastogenesis in Human Tunica Albuginea-Derived Fibroblasts Part 2: Interference in a TGF-β1/Smad-Dependent Mechanism and Downregulation of AAT1

Authors


Guiting Lin, MD, PhD, Department of Urology, University of California, San Francisco, 400 Parnassus St., Campus Box 0738, San Francisco California, 94143-0738, United States. Tel: (415) 476-2106; Fax: (415) 476-8849; E-mail: glin@urology.ucsf.edu

ABSTRACT

Introduction.  Transforming growth factor-beta1 (TGF-β1) contributes to the pathogenesis of Peyronie's disease (PD). Pentoxifylline (PTX) antagonizes the effects of TGF-β1 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-β1 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-β1 and PTX as monotherapy at differing concentrations and time points. Combination treatment (TGF-β1 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-β1 increased messenger ribonucleic acid (mRNA) and protein expression of elastin in a time-dependent fashion in TADF. PTX did not interfere with TGF-β1 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-β1. PTX has no effect on elastin production but attenuates elastogenesis in TADF through an AAT1-related mechanism. Lin G, Shindel AW, Banie L, Ning H, Huang YC, Liu G, Lin CS, and Lue TF. Pentoxifylline attenuates TGF-β1-stimulated elastogenesis in human tunica albuginea-derived fibroblasts Part 2: interference in a TGF-β1/Smad-dependent mechanism and downregulation of aat1. J Sex Med 2010;7:1787–1797.

Get access to the full text of this article

Ancillary