Abstract
Intraurethral inoculation of mice with uropathogenic Escherichia coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of a mast cell stabilizer, cromolyn sodium, and the histamine 1 receptor antagonist cetirizine di-hydrochloride in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.
| Original language | English (US) |
|---|---|
| Pages (from-to) | F466-F479 |
| Journal | American Journal of Physiology - Renal Physiology |
| Volume | 321 |
| Issue number | 4 |
| DOIs | |
| State | Published - Sep 2021 |
Funding
This work was supported by the National Institute of Diabetes and Digestive and Kidney Grants R01DK083609 (to P.T.) and R01DK117906 (to Dr. Simon W. Hayward and P.T.). We thank Dr. Simon W. Hayward (Department of Surgery, NorthShore University HealthSystem, Evanston, IL) for providing insights into the project and providing some of the initial human patient prostate sections for characterizing and standardizing the staining in human tissues. Histology services were provided by the Northwestern University Research Mouse Histology and Phenotyping Laboratory, which is supported by the National Cancer Institute Grant P30CA060553 (awarded to the Robert H Lurie Comprehensive Cancer Center). Flow cytometry services were provided by the Northwestern University Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility, which is supported by a Cancer Center Support Grant (NCI Grant CA060553).
Keywords
- Fibrosis
- Inflammation
- Mast cell
- Prostate
- Smooth muscle cell contraction
ASJC Scopus subject areas
- Physiology