Histologic inflammation and collagen content are not positively correlated in human BPH.

INTRODUCTION: Recent clinical studies have implicated prostate inflammation and fibrosis in the development of bladder outlet obstruction and lower urinary tract symptoms (LUTS). Studies utilizing rodent models, including work in our laboratory, have shown prostate fibrosis to occur as a consequence of inflammation. However, the relationship between collagen content and inflammation in human tissue samples obtained from surgical treatment of benign prostatic hypererplasia (BPH)/LUTS has not to our knowledge been previously examined. METHODS: Prostate tissue specimens from 53 patients (ages 47-88, mean 65.1) treated by open simple prostatectomy or transurethral resection of the prostate for BPH/LUTS were stained to quantitatively assess prostate inflammation and collagen content. Patients with prostate cancer present in greater than 5% of the surgical specimen were excluded. Prostate volume was determined from pelvic CT scan obtained within 2 years of surgery. RESULTS: Analysis of the data showed that inflammation was inversely correlated with collagen content (r = -0.28, p = 0.04). In men with prostates less than 75 cm3 inflammation increases and collagen content decreases with prostate volume (p = 0.002 and p = 0.03, respectively) while in men with prostate volume over 75 cm3 inflammation decreases and collagen content increases with prostate volume (p = 0.30 and p = 0.005, respectively). CONCLUSIONS: Our data do not support the assumed positive association of prostate inflammation with collagen content. Coordinated analysis of scatter plots of inflammation and collagen content with prostate volume revealed a subset of prostates with volumes >50 cm3 prostate characterized by intense inflammation and low collagen content and it is this subgroup that appears most responsible for the inverse correlation of inflammation and collagen.

Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis.

BACKGROUND: Prostatic inflammation has been suggested to contribute to the etiology of lower urinary tract symptoms by inducing fibrosis. We previously used a well-characterized mouse model of bacterial-induced prostate inflammation to demonstrate that chronic prostatic inflammation induces collagen deposition. Here, we examined stability of the newly synthesized collagen in bacterial-induced prostatic inflammation and the reversibility of fibrosis after resolution of infection and inflammation. METHODS: Uropathogenic Escherichia coli 1677 was instilled transurethrally into adult C3H/HeOuJ male mice to induce chronic prostatic inflammation. Collagen was labeled by (3) H-proline administration for 28 days post-inoculation and (3) H-hydroxyproline incorporation measured to determine stability of the newly synthesized collagen. Inflammation score was graded using a previously established system and total collagen content was measured by picrosirius red staining quantitation and hydroxyproline content. Resolution of inflammation and reversal of collagen deposition was assessed after treatment with antibiotic enrofloxacin for 2 weeks on day 28 post-inoculation followed by an 8-week recovery period. RESULTS: Decay analysis of incorporated (3) H-hydroxyproline revealed the half-life of newly synthesized collagen to be significantly shorter in infected/inflamed prostates than in controls. Treatment with antibiotic enrofloxacin completely eradicated bacterial infection and allowed resolution of inflammation. This was followed by marked attenuation of collagen content and correlation analysis verified a positive association between the resolution of inflammation and the reversal of collagen deposition. CONCLUSIONS: These data demonstrate, for the first time, that inflammation-induced prostatic fibrosis is a reversible process.

Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening.

In animal models, chemical disruption of the Hedgehog (Hh) signaling pathway during embryonic development causes severe birth defects including holoprosencephaly and cleft lip and palate. The exact etiological basis of correlate human birth defects remains uncertain but is likely multifactorial, involving the interaction of genetic and environmental or chemical influences. The Hh transduction mechanism relies upon endogenous small molecule regulation, conferring remarkable pathway sensitivity to inhibition by a structurally diverse set of exogenous small molecules. Here, we employed small molecule screening to identify human exposure-relevant Hh signaling inhibitors. From a library of 4240 compounds, including pharmaceuticals, natural products, and pesticides, three putative Hh pathway inhibitors were identified: tolnaftate, an antifungal agent; ipriflavone, a dietary supplement; and 17-beta-estradiol, a human hormone and pharmaceutical agent. Each compound inhibited Hh signaling in both mouse and human cells. Dose-response assays determined the three compounds to be 8- to 30-fold less potent than the index Hh pathway inhibitor cyclopamine. Despite current limitations in chemical library availability, which narrowed the scope of this study to only a small fraction of all human exposure-relevant small molecules, three structurally diverse environmental Hh signaling inhibitors were identified, highlighting an inherent pathway vulnerability to teratogenic influences.