Introduction Postprostatectomy erectile dysfunction (ED) is thought to be due primarily to injury to cavernous nerve (CN) during surgery. The molecular mechanisms leading to ED after CN injury are poorly understood. Aim We determined whether transforming growth factor-β1 (TGF-β1), sphingosine-1-phosphate (S1P) and RhoA/Rho-kinase (ROCK) signaling pathways were involved in corporal fibrosis after bilateral CN injury in rats. Methods Forty-eight 10-week-old male Sprague-Dawley rats were equally divided into the following four groups: normal control group (C); sham surgery group (S); bilateral CN crush injury group (I); and bilateral CN transection group (T). Within each of the four groups, two subgroups were analyzed as a function of time (1 and 8 weeks postoperatively). Main Outcome Measures Penile tissue was processed for immunoblot (RhoA, ROCK1, phospho-myosin phosphatase target subunit [MYPT1]), reverse transcription-polymerase chain reaction (RT-PCR) (TGF-β1, sphingosine kinase type 1 [SphK1], and S1P2), immunohistochemistry (alpha smooth muscle actin [α-SMA]), and Masson’s trichrome staining. Results At 1 and 8 weeks postoperatively, the I and T groups had a significantly decreased smooth muscle cell/collagen ratio, the expression of α-SMA and phospho-MYPT1 compared to the C group. Densitometry revealed a significantly higher expression of RhoA and ROCK1 in the T group compared to the C group at 1 and 8 weeks postoperatively. For the I group, the expression of RhoA significantly increased starting from 1 week postoperatively, but the expression of ROCK1 significantly increased as late as 8 weeks following injury. The expression of TGF-β1 and S1P2 mRNA in the I or T group remained significantly increased up to 8 weeks compared to the C group, despite significant reduction at 8 weeks compared to 1 week postoperatively. The expression of SphK1 mRNA in the I and T groups was significantly increased at 1 week but not 8 weeks postoperatively. Conclusions Our data suggest that S1P and RhoA/ROCK1 signaling may be involved in corporal fibrosis associated with loss of smooth muscle through coordination with TGF-β1 after CN injury.

Cervical carcinoma is the predominant cancer among malignancies in women throughout the world, and human papillomavirus (HPV) 16 is the most common agent linked to human cervical carcinoma. The present study was performed to investigate the mechanisms of immune escape in HPV-induced cervical cancer cells. The presence of HPV oncoproteins E6 and E7 in the extracellular fluids of HPV-containing cervical cancer cell lines SiHa and CaSki was demonstrated by ELISA. The effect of HPV 16 oncoproteins E6 and E7 on the production of IFN-γ by IL-18 was assessed. E6 and E7 proteins reduced IL-18-induced IFN-γ production in both primary PBMCs and the NK0 cell line. FACS analysis revealed that the viral oncoproteins reduced the binding of IL-18 to its cellular surface receptors on NK0 cells, whereas there was no effect of oncoproteins on IL-1 binding to its surface IL-1 receptors on D10S, a subclone of the murine Th cell D10.G4.1. In vitro pull-down assays also revealed that the viral oncoproteins and IL-18 bound to IL-18R α-chain competitively. These results suggest that the extracellular HPV 16 E6 and E7 proteins may inhibit IL-18-induced IFN-γ production locally in HPV lesions through inhibition of IL-18 binding to its α-chain receptor. Down-modulation of IL-18-induced immune responses by HPV oncoproteins may contribute to viral pathogenesis or carcinogenesis.

To understand modulation of a novel immune-related cytokine, interleukin-18, by human papillomavirus type (HPV) 16 oncogenes, HaCaT, normal keratinocyte cell line, and C-33A, HPV-negative cervical cancer cell line, were prepared to establish stable cell lines expressing E6, E6 mutant (E6m), E6E7, or E7 constitutively. Expressions of various HPV oncogene transcripts were identified by RT-PCR. Expression of HPV oncogene E6 was reversely correlated to the expression of interleukin-18, a novel pro-inflammatory cytokine. The expression of E6 in C-33A, independent of E6 splicing, resulted in decreased IL-18 expression and that of IL-18 was also significantly reduced in HaCaT cells expressing E6. The level of p53 was reduced in C-33A cells expressing E6 whereas not altered in HaCaT cells expressing E6, suggesting that E6 downregulated IL-18 expression via an independent pathway of p53 degradation in HaCaT cells which have a mutated p53 form. However, E7 did not affect IL-18 expression significantly in both C-33A and HaCaT cells. Cotransfection experiments showed that E6 oncogene did not inhibit the activities of IL-18 promoter P1 and P2, suggesting that E6 oncogene indirectly inhibited IL-18 expression. Taken together, E6, E6m and E6/E7 inhibited IL-18 expression with some variation, assuming that cells expressing E6 oncogene can evade immune surveillance by downregulating the expression of immune stimulating cytokine gene, IL-18, and inhibiting the cascade of downstream effects that follow activation of the IL-18 receptor. ß

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Our data suggest that early inhibition of Rho-kinase after cavernous nerve crush injury may prevent corporal apoptosis and fibrosis by suppressing the Akt/Bad/Bax/caspase-3 and LIMK2/cofilin pathways, preventing corporal veno-occlusive dysfunction and erectile dysfunction.

The ROCK1/LIMK2/cofilin pathway may be involved in ED related to corporal fibrosis, and it appears to be functional particularly in the early period after CN injury.

Our data suggest that HoLEP is effective in improving micturition, but de novo postoperative UI occurred in some patients although usually transient. Surgeons should be careful to not injure the bladder mucosa during morcellation.

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