Objectives: To compare effects of repairing injured tunica albuginea (PTA) of rat penis by single or repeated local injections of chlorhexidine ethanol (ChE) into the PTA and to establish a new animal model of Peyronie's disease (PD). Materials and Methods: Forty-two rats were divided into 7 groups. Rats either served as the normal control group with 1-5 injections of 0.9% saline or they received a single injection, 2, 3, 4, or 5 injections of ChE (0.1% chlorhexidine gluconate plus 15% ethanol dissolved in saline); rats in the positive control group were injected with TGF-β1. At 60 days after the last injection, the intracavernous pressure, degree of penile curvature, and histology were evaluated. Results: Compared with the single injection of the ChE group, we found the following in the repeat ChE injections groups: an increase in the degree of penile curvature, fibrous plaques in the PTA and/or corpus cavernosum, broken elastic fibers, slightly decreased erectile function, and an increased expression of TGF-β1 and αSMA. Conclusions: Repeated ChE injuries of PTA may lead to fibrosis. This represents an excellent model of PD that involves repeated injections of ChE into the local PTA as well as reveals the pathophysiologic mechanism of PD.

1.
Yafi FA, Pinsky MR, Sangkum P, Hellstrom WJ: Therapeutic advances in the treatment of Peyronie's disease. Andrology 2015;3:650-660.
2.
Ziegelmann MJ, Viers BR, McAlvany KL, Bailey GC, Savage JB, Trost LW: Restoration of penile function and patient satisfaction with intralesional collagenase clostridium histolyticum injection for Peyronie's disease. J Urol 2016;195:1051-1056.
3.
Shaw EJ, Mitchell GC, Tan RB, Sangkum P, Hellstrom WJ: The non-surgical treatment of peyronie disease: 2013 update. World J Mens Health 2013;31:183-192.
4.
Gelbard MK, Dorey F, James K: The natural history of Peyronie's disease. J Urol 1990;144:1376-1379.
5.
Martinez-Salamanca JI, Egui A, Moncada I, Minaya J, Ballesteros CM, Del Portillo L, et al: Acute phase Peyronie's disease management with traction device: a nonrandomized prospective controlled trial with ultrasound correlation. J Sex Med 2014;11:506-515.
6.
Nelson CJ, Mulhall JP: Psychological impact of Peyronie's disease: a review. J Sex Med 2013;10:653-660.
7.
Hashimoto K, Hisasue S, Kato R, Kobayashi K, Shimizu T, Tsukamoto T: Outcome analysis for conservative management of Peyronie's disease. Int J Urol 2006;13:244-247.
8.
Rosen R, Catania J, Lue T, Althof S, Henne J, Hellstrom W, et al: Impact of Peyronie's disease on sexual and psychosocial functioning: qualitative findings in patients and controls. J Sex Med 2008;5:1977-1984.
9.
Bjekic MD, Vlajinac HD, Sipetic SB, Marinkovic JM: Risk factors for Peyronie's disease: a case-control study. BJU Int 2006;97:570-574.
10.
Jarow JP, Lowe FC: Penile trauma: an etiologic factor in Peyronie's disease and erectile dysfunction. J Urol 1997;158:1388-1390.
11.
Zargooshi J: Trauma as the cause of Peyronie's disease: penile fracture as a model of trauma. J Urol 2004;172:186-188.
12.
Gonzalez-Cadavid NF, Rajfer J: Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie's disease. Nat Clin Pract Urol 2005;2:291-297.
13.
Margadant C, Sonnenberg A: Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep 2010;11:97-105.
14.
Bivalacqua TJ, Diner EK, Novak TE, Vohra Y, Sikka SC, Champion HC, et al: A rat model of Peyronie's disease associated with a decrease in erectile activity and an increase in inducible nitric oxide synthase protein expression. J Urol 2000;163:1992-1998.
15.
Piao S, Ryu JK, Shin HY, Zhang L, Song SU, Han JY, et al: Repeated intratunical injection of adenovirus expressing transforming growth factor-beta 1 in a rat induces penile curvature with tunical fibrotic plaque: a useful model for the study of Peyronie's disease. Int J Androl 2008;31:346-353.
16.
Ke CY, Lee CC, Lee CJ, Subeq YM, Lee RP, Hsu BG: Aliskiren ameliorates chlorhexidine digluconate-induced peritoneal fibrosis in rats. Eur J Clin Invest 2010;40:301-309.
17.
Lee CJ, Subeq YM, Lee RP, Ke CY, Lin NT, Hsu BG: Beneficial effects of enalapril on chlorhexidine digluconate-induced liver peritoneal fibrosis in rats. Chin J Physiol 2011;54:225-234.
18.
Ro Y, Hamada C, Inaba M, Io H, Kaneko K, Tomino Y: Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats. Nephrol Dial Transplant 2007;22:2838-2848.
19.
Qiu X, Lin H, Wang Y, Yu W, Chen Y, Wang R, et al: Intracavernous transplantation of bone marrow-derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats. J Sex Med 2011;8:427-436.
20.
Kimura K, Ando K, Ohnishi H, Ishikawa T, Kakumu S, Takemura M, et al: Immunopathogenesis of hepatic fibrosis in chronic liver injury induced by repeatedly administered concanavalin A. Int Immunol 1999;11:1491-1500.
21.
El-Sakka AI, Hassan MU, Nunes L, Bhatnagar RS, Yen TS, Lue TF: Histological and ultrastructural alterations in an animal model of Peyronie's disease. Br J Urol 1998;81:445-452.
22.
Nehra A, Gettman MT, Nugent M, Bostwick DG, Barrett DM, Goldstein I, et al: Transforming growth factor-beta1 (TGF-beta1) is sufficient to induce fibrosis of rabbit corpus cavernosum in vivo. J Urol 1999;162(3 pt 1):910-915.
23.
Ryu JK, Song SU, Han JY, Chu YC, Lee M, Kim JS, et al: Establishment of penile fibrosis model in a rat using mouse NIH 3T3 fibroblasts expressing transforming growth factor beta1. Biol Reprod 2005;72:916-921.
24.
Somers KD, Dawson DM: Fibrin deposition in Peyronie's disease plaque. J Urol 1997;157:311-315.
25.
Davila HH, Ferrini MG, Rajfer J, Gonzalez-Cadavid NF: Fibrin as an inducer of fibrosis in the tunica albuginea of the rat: a new animal model of Peyronie's disease. BJU Int 2003;91:830-838.
26.
Chung E, De Young L, Brock GB: Rat as an animal model for Peyronie's disease research: a review of current methods and the peer-reviewed literature. Int J Impot Res 2011;23:235-241.
27.
Lucattelli M, Lunghi B, Fineschi S, Mirone V, d'Emmanuele di Villa Bianca R, Longo N, et al: A new mouse model of Peyronie's disease: an increased expression of hypoxia-inducible factor-1 target genes during the development of penile changes. Int J Biochem Cell Biol 2008;40:2638-2648.
28.
El-Sakka AI, Selph CA, Yen TS, Dahiya R, Lue TF: The effect of surgical trauma on rat tunica albuginea. J Urol 1998;159:1700-1707.
29.
Acikgoz A, Gokce E, Asci R, Buyukalpelli R, Yilmaz AF, Sarikaya S: Relationship between penile fracture and Peyronie's disease: a prospective study. Int J Impot Res 2011;23:165-172.
30.
Zargooshi J: Sexual function and tunica albuginea wound healing following penile fracture: an 18-year follow-up study of 352 patients from Kermanshah, Iran. J Sex Med 2009;6:1141-1150.
31.
Amer T, Wilson R, Chlosta P, AlBuheissi S, Qazi H, Fraser M, Aboumarzouk OM: Penile fracture: a meta-analysis. Urol Int 2016;96:315-329.
32.
Ferretti L, Fandel TM, Qiu X, Zhang H, Orabi H, Wu AK, et al: Tunica albuginea allograft: a new model of LaPeyronie's disease with penile curvature and subtunical ossification. Asian J Androl 2014;16:592-596.
33.
Bonventre JV: Primary proximal tubule injury leads to epithelial cell cycle arrest, fibrosis, vascular rarefaction, and glomerulosclerosis. Kidney Int Suppl (2011) 2014;4:39-44.
34.
Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, et al: Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 2014;505:97-102.
35.
Borkham-Kamphorst E, Drews F, Weiskirchen R: Induction of lipocalin-2 expression in acute and chronic experimental liver injury moderated by pro-inflammatory cytokines interleukin-1β through nuclear factor-κB activation. Liver Int 2011;31:656-665.
36.
de Vries DK, Lindeman JH, Tsikas D, de Heer E, Roos A, de Fijter JW, et al: Early renal ischemia-reperfusion injury in humans is dominated by IL-6 release from the allograft. Am J Transplant 2009;9:1574-1584.
37.
Abraham DJ, Eckes B, Rajkumar V, Krieg T: New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Curr Rheumatol Rep 2007;9:136-143.
38.
Ejeil AL, Igondjo-Tchen S, Ghomrasseni S, Pellat B, Godeau G, Gogly B: Expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy and diseased human Gingiva. J Periodontol 2003;74:188-195.
39.
Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, et al: Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal 2007;19:761-771.
40.
Gong R, Rifai A, Tolbert EM, Centracchio JN, Dworkin LD: Hepatocyte growth factor modulates matrix metalloproteinases and plasminogen activator/plasmin proteolytic pathways in progressive renal interstitial fibrosis. J Am Soc Nephrol 2003;14:3047-3060.
41.
Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al: Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013;19:1617-1624.
42.
Derynck R, Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-584.
43.
Jiang HS, Zhu LL, Zhang Z, Chen H, Chen Y, Dai YT: Estradiol attenuates the TGF-beta 1-induced conversion of primary TAFs into myofibroblasts and inhibits collagen production and myofibroblast contraction by modulating the Smad and Rho/ROCK signaling pathways. Int J Mol Med 2015;36:801-807.
44.
Chung E, De Young L, Brock GB: Penile duplex ultrasonography in men with Peyronie's disease: is it veno-occlusive dysfunction or poor cavernosal arterial inflow that contributes to erectile dysfunction? J Sex Med 2011;8:3446-3451.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.