elastin and Penile-Induration

Peyronie's disease (PD) is a connective tissue disorder of the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the disease in its active phase.. To test the effects of a local injection of adipose tissue-derived stem cells (ADSCs) in the active phase of a rat model of PD on the subsequent development of fibrosis and elastosis of the TA and underlying erectile tissue.. A total of 27 male 12-wk-old Sprague-Dawley rats were divided in three equal groups and underwent injection of vehicle (sham), 0.5-μg [corrected] transforming growth factor (TGF)-β1 in a 50-μl vehicle in either a PD or a PD plus ADSC group in the dorsal aspect of the TA.. The sham and PD groups were treated 1 d after TGF-β1 injection with intralesional treatment of vehicle, and the PD plus ADSC group received 1 million human-labeled ADSCs in the 50-μl vehicle. Five weeks after treatment, six rats per group underwent erectile function measurement. Following euthanasia, penises were harvested for histology and Western blot.. The ratio of intracavernous pressure to mean arterial pressure (ICP/MAP) upon cavernous nerve stimulation, elastin, and collagen III protein expression and histomorphometric analysis of the penis. Statistical analysis was performed by analysis of variance followed by the Tukey-Kramer test for post hoc comparisons or the Mann-Whitney test when applicable.. Erectile function significantly improved after ADSC treatment (ICP/MAP 0.37 in PD vs 0.59 in PD plus ADSC at 5-V stimulation; p=0.03). PD animals developed areas of fibrosis and elastosis with a significant upregulation of collagen III and elastin protein expression. These fibrotic changes were prevented by ADSC treatment.. This study is the first to test stem cell therapy in an animal model of PD. Injection of ADSCs into the TA during the active phase of PD prevents the formation of fibrosis and elastosis in the TA and corpus cavernosum.

Topics: Adipose Tissue; Animals; Biomarkers; Collagen Type III; Elasticity; Elastin; Erectile Dysfunction; Fibrosis; Humans; Injections, Intralesional; Male; Penile Erection; Penile Induration; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation; Transplantation, Heterologous; Treatment Outcome

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.. We studied cell-signaling pathways through which TGF-beta1 and PTX mediate collagen metabolism, elastin expression, and elastogenesis in tunica albuginea-derived fibroblasts (TADFs).. 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.. 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.. 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.. 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.

Topics: Blotting, Western; Carrier Proteins; Collagen; Dose-Response Relationship, Drug; Down-Regulation; Elastic Tissue; Elastin; Fibroblasts; Gene Expression; Humans; Male; Penile Induration; Penis; Pentoxifylline; Phosphodiesterase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1

This study was undertaken to establish a Peyronie's disease model with penile curvature by using recombinant transforming growth factor-beta1 (TGF-beta1) protein or adenovirus (ad-TGF-beta1). Four-month-old male Sprague-Dawley rats were divided into seven groups (n = 18 per group): G1 received a single injection of saline into the tunica albuginea (0.1 mL); G2, repeated injections of ad-LacZ (days 0, 3, and 6; 1 x 10(10) particles/0.1 mL respectively); G3, a single injection of recombinant TGF-beta1 protein (700 ng/0.1 mL); G4, repeated injections of recombinant TGF-beta1 protein (days 0, 3 and 6; 700 ng/0.1 mL respectively); G5, a single injection of low-dose ad-TGF-beta1 (1 x 10(10) particles/0.1 mL); G 6, a single injection of high-dose ad-TGF-beta1 (3 x 10(10) particles/0.1 mL); and G7, repeated injections of low-dose ad-TGF-beta1 (days 0, 3, and 6; 1 x 10(10) particles/0.1 mL respectively). Penile curvature was evaluated 30, 45 and 60 days after treatment, and the penis was then harvested for histological examination. Repeated injection of low-dose ad-TGF-beta1 not only induced fibrous scar in the tunica, which lasted up to 60 days after injection, but also resulted in significant penile curvature by artificial erection test 45 days after treatment. A peculiar histological finding in this group was trapping of inflammatory cells in the tunica, subsequent fibrosis, and formation of cartilage and calcification as well as loss of elastin fibres. This model involving repeated injection of ad-TGF-beta1 may contribute to further investigation of the pathogenesis of Peyronie's disease and the development of new therapeutics targeting this pathway.

Topics: Adenoviridae; Animals; Calcinosis; Cartilage; Disease Models, Animal; Disease Progression; Elastin; Fibrosis; Gene Transfer Techniques; Genetic Vectors; Injections; Male; Penile Erection; Penile Induration; Penis; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Swine; Time Factors; Transforming Growth Factor beta1

Peyronie's disease is a pathological fibrosis characterized by excessive deposition of collagen in the plaque. Although the etiology of Peyronie's disease is unknown, trauma has been hypothesized as the inciting event. In an effort to obtain more insight into the pathogenesis of Peyronie's disease plaque tissue was examined for collagen, elastic fiber, and fibrin content and distribution.. Plaque tissue specimens from 33 patients with Peyronie's disease, control penile tissue and nodular tissue from 8 patients with Dupuytren's contracture were analyzed histochemically for collagen staining and elastic fiber structure and distribution. Plaque tissue from 19 Peyronie's disease patients, control tissue and nodular tissue from Dupuytren's disease were also analyzed for the presence of fibrin by histochemical staining and immunoblotting.. Aberrantly stained collagen was detected in 32 of 33 plaque specimens (97%) and disrupted elastic fibers in 31 of the same specimens (94%). Fibrin deposition was detected histochemically in plaque tissue from 18 of 19 patients (95%) but it was not detectable in normal or scarred tunica from control patients. The presence of authentic fibrin accumulation in plaque tissue was confirmed by immunoblot analysis but fibrin was not detected in dermal tissue extracts from the same patient. Aberrant collagen staining and fibrin deposition were detected in nodular tissue from 7 of 8 Dupuytren's contracture patients (88%) and altered elastic fibers in 5 of the same patients (63%).. Deposition of fibrin in plaque tissue is consistent with the hypothesis that repetitive microvascular injury results in fibrin deposition in the tissue space and has served to provide insights into the pathophysiology of Peyronie's disease. We propose a model that accounts for the clinical and biological features of Peyronie's disease.

Topics: Adult; Aged; Collagen; Elastin; Fibrin; Fibrosis; Humans; Male; Middle Aged; Penile Induration

The cause of Peyronie's disease is unknown. Immunological mechanisms in the pathogenesis have been previously suggested. Antibodies to elastin are present in all individuals. However, abnormal serum levels of anti-tropoelastin (reflecting elastin synthesis) and anti-alpha-elastin (reflecting elastin destruction) are seen in a variety of autoimmune diseases. We show that patients with Peyronie's disease have higher levels of antibodies to tropoelastin (p < 0.047) and alpha-elastin (p < 0.012) than age-matched controls, suggesting an increase in elastin synthesis and breakdown, respectively. These findings suggest the presence of autoimmune mechanisms in the pathogenesis of Peyronie's disease, which may have future diagnostic and therapeutic implications.

Topics: Antibodies; Autoimmune Diseases; Collagen; Elastin; Enzyme-Linked Immunosorbent Assay; Humans; Male; Penile Induration; Tropoelastin