COX2 is important mediator to development of bladder overactivity after prostatic inflammation

Mizoguchi S1, Mori K2, Kurobe M1, Saito T1, Gotoh D1, Cao N1, Alexandre E1, Mimata H2, DeFranco D1, Wang Z1, Yoshimura N1

Research Type

Basic Science / Translational

Abstract Category

Male Lower Urinary Tract Symptoms (LUTS) / Voiding Dysfunction

Abstract 782
Non Discussion Abstract
Scientific Non Discussion Abstract Session 37
Benign Prostatic Hyperplasia (BPH) Overactive Bladder Animal Study
1.University of Pittsburgh, 2.Oita University
Links

Abstract

Hypothesis / aims of study
There is increasing evidence suggesting positive correlation between prostatic inflammation and lower urinary tract symptoms (LUTS) in male with benign prostatic hyperplasia (BPH) [1]. However, the underlying mechanism is still unclear. Recent studies have reported that chronic inflammation in BPH tissues is significantly associated with focal upregulation of cyclooxygenase-2 (COX2) in the glandular epithelium and that an addition of a COX2 inhibitor to α-blockers had a greater decrease in average overactive bladder symptoms score (OABSS) in patients with BPH [2]. Furthermore, increased mast cell activity is reportedly associated with pathophysiology of BPH and degree of male LUTS [3]. Therefore, prostatic inflammation mediated by COX2 and mast cell activation in the prostate are possibly implicated to development of LUTS and OAB symptoms in BPH patients. Therefore, in the present study, to elucidate the role of COX2-mediated prostatic inflammation and mast cells, we investigated changes in voiding function, prostatic inflammation and mast cell activity in the prostate using a rat model with chemically induced prostatic inflammation.
Study design, materials and methods
Male Spraque-Dewley rats were divided into three groups; (1) Sham group (sham operation with placebo administration, n=6), (2) Prostatic inflammation group (formalin injection with placebo administration, n=6) and (3) Treatment group (formalin injection with cerecoxib (COX2 inhibitor) treatment, n=6). Prostatic inflammation was induced by formalin (5%; 50 µl per lobe) injection into bilateral ventral lobes of the prostate while the Sham group had saline injection into the ventral prostate as sham operation. Two days before induction of prostatic inflammation, Treatment group had cerecoxib administration orally at 10 mg/kg/day for thirty days. Four week after induction of prostatic inflammation, bladder function was evaluated by awake cystometry. After cystometry, the ventral prostate was harvested to examine gene expression of IL1β and COX2 as well as changes in morphology and mast cell activity by hematoxylin and eosin staining (HE) and toluidine blue staining (TB). The number of mast cells was counted at an x 400 field using 5 random fields from 4 different rats in each group. Mast cell activity was defined as a relative number of degranulated mast cells to the total mast cells.
Results
Compared to Sham group, Prostatic inflammation group demonstrated significant shorter intercontraction intervals (ICI), but not Treatment group. Other cystometric parameters were not significantly different among groups. In evaluation of gene expressions in the prostate, IL1β and COX2 were significantly increased in Prostatic inflammation group compared to Sham group (Fig.1). After treatment with the COX2 inhibitor, mRNA expression in IL1β and COX2 were decreased to the same level as in Sham group (Fig.1). HE staining demonstrated intact glandular epithelium and stroma in Sham group while there were acini with abnormal structure and stromal extension with fibrosis in Prostatic inflammation group. Treatment group showed lesser stromal extension and abnormal acini. In TB staining for mast cell detection, there was an increase in the relative number of degranulated mast cells normalized to the total mast cell number in Prostatic inflammation group compared to Sham group (Fig.2). Treatment group also exhibited significantly increased mast cell activity compared to Sham group, but mast cell activation after COX2 inhibition was significantly decreased compared to Prostatic inflammation group (Fig.2).
Interpretation of results
Rats with formalin induced prostatic inflammation demonstrated the bladder overactive condition as evidenced by shorter ICI in association with, in the prostate, upregulation of IL1β and COX2 gene expression and increased mast cell activity supported shown by the increased number of degranulated mast cells.  Furthermore, COX2 inhibition improved bladder overactivity as well as prostatic inflammation in association with stabilization of mast cells, which are reportedly to be significantly related to the severity of male LUTS in BPH patients[3]. These findings suggest that prostatic inflammation mediated by COX2 can induce mast cell activation, leading to bladder overactivity after prostatic inflammation.
Concluding message
COX2 inhibition improved bladder overactivity and mast cell activity induced by prostatic inflammation. Therefore, further clarification of the relationship between bladder overactivity and prostatic inflammation mediated by COX2 and mast cell activation could be useful for the development of new treatments for LUTS in BPH patients with prostatic inflammation.
Figure 1
Figure 2
References
  1. Nickel, J.C., et al., The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol, 2008. 54(6): p. 1379-84.
  2. Wang, W., et al., Chronic inflammation in benign prostate hyperplasia is associated with focal upregulation of cyclooxygenase-2, Bcl-2, and cell proliferation in the glandular epithelium, Prostate. 2004 Sep 15;61 (1) : p. 60-72.
  3. Ou, Z., et al., Infiltrating mast cells enhance benign prostatic hyperplasia through IL-6/STAT3/Cyclin D1 signals, Oncotarget. 2017 Jul 22;8(35) : p. 59156-59164.
Disclosures
<span class="text-strong">Funding</span> U54 DK112079 <span class="text-strong">Clinical Trial</span> No <span class="text-strong">Subjects</span> Animal <span class="text-strong">Species</span> Rat <span class="text-strong">Ethics Committee</span> University of Pittsburgh Institutional Animal Care and Use Committe