Hypothesis / aims of study
Lower urinary tract symptoms (LUTS) represent one of the most common and bothersome conditions seen in daily urologic practice, affecting at least one in every four men older than 40 years.1 The morphological features of the prostate and benign prostate enlargement (BPE) are well known to be associated with LUTS and lower urinary tract dysfunction (LUTD) in the male patients. The morphological features of the prostate include intravesical prostatic protrusion (IPP), which is defined as distance from protruded prostate to the base of bladder. The higher IPP increased International Prostate Symptoms Score (IPSS) and worsened bladder outlet obstruction (BOO) evaluated by pressure-flow urodynamic studies (Int J of Urology 2006 LIM, J Urol IPP BOO). The BPE is also well known to be associated with BOO in the male patients (urology prostate volume LUTS). The several risk factors for the development of BPE have been identified. These include age, genetics, hormones, growth factors, inflammation, and metabolic syndrome. However, the precise molecular etiology of prostate related with BOO is complicated and poorly understood. This study aims to find out the novel mechanism underlying BOO by comprehensive gene expression analysis (CGEA).
Study design, materials and methods
A total of 31 patients who had a diagnosis of benign by the random prostate biopsy were enrolled in this study. CGEA was performed with prostate specimens obtained by the biopsy. The patients were divided into control group (prostate volume < 30 mL) and benign prostatic enlargement (BPE) group (prostate volume ≥ 30 mL). Hierarchical clustering was performed to identify the clusters with similar gene expression by the genes indicated significantly different between two groups by t-test. The histological examinations and uroflowmetry parameters were compared among each cluster by Mann-Whitney's U test. The protocol was approved by the ethics committee of Fukushima Medical University
Results
CGEA selected 12 genes with significant difference in mean converted value between control and BPE (P<0.01) from 11,907 genes. Hierarchical clustering analysis using these 12 genes categorized three different clusters: the control (n=8), the BPE (n=11) and BPE with inflammatory (n=12) clusters. As compared BPE cluster, the BPE with humoral immunity cluster promotes B cell infiltration (increased VSIG2 gene), and activates B cells (reduced MSMB gene). In the histological examination, the numbers of M1 macrophages and B cells were significantly greater in the BPE with humoral immunity cluster than in the other clusters (M1 macrophages: control 1.6 ± 0.6 numbers/area, BPE 1.3 ± 0.7 numbers/area, BPE with humoral immunity 6.1 ± 2.2 numbers/area, control vs BPE with inflammatory P<0.01, BPE vs BPE with inflammatory P<0.01. B cells: control 0.2 ± 0.2 numbers/area, BPE 0.4 ± 0.3 numbers/area, BPE with humoral immunity 8.0 ± 4.0 numbers/area, control vs BPE with inflammatory P<0.01, BPE vs BPE with inflammatory P<0.01). The collagen/muscle was significantly increased in the BPE with humoral immunity cluster as compared with other clusters (control 13.4 ± 14.6 %, BPE 11.9 ± 6.5 %, BPE with humoral immunity 61.6 ± 28.7 %, control vs BPE with inflammatory P=0.04, BPE vs BPE with inflammatory P<0.01.). The maximum flow rate was significantly lower in the BPE with inflammatory cluster than in the control cluster (control vs BPE with inflammatory, 18.3 ± 3.6 mL/sec vs 10.4 ± 5.5 mL/sec P=0.03). There was no significant difference about the maximum flow rate between control cluster and BPE cluster.
Interpretation of results
In this study, CGEA indicated that increased VSIG2 and decreased MSMB genes in the BPE with humoral immunity. VSIG2, which was expressed in the M1 macrophage, promotes B cells infiltration. MSMB, which was synthesized in the prostatic epithelial cells, suppressed activation of B cells. Histological examination also showed increased M1 macrophages and B cells in the BPE with humoral immunity group. In the Elastica Masson staining, the collagen/muscle was significantly increased in the BPE with humoral immunity group. In the uroflowmetry parameters, the maximum flow rate was significantly lower in the BPE with humoral immunity group than in the control group. These results suggested that Inflammation by activated humoral immunity cause prostate fibrosis, resulting in the BOO throught the increased urethral resistance.