Abstract
Introduction
Benign Prostatic Hyperplasia (BPH) is characterized by nonmalignant enlargement of glandular and stromal compartments, inflammation, and tissue remodeling. BPH progression can produce lower urinary tract symptoms (LUTS) through urethral compression. However, the mechanisms driving BPH progression remain incompletely understood, highlighting the need to identify pathological mechanisms that may provide additional therapeutic targets beyond symptom management. Recent studies identified increased lipid accumulation and lipid-laden macrophages (foam cells) within the prostatic lumen as previously underrecognized pathological features. These findings raise an important mechanistic question: what drives macrophage recruitment and foam-cell formation within the prostatic lumen? In atherosclerosis, oxidation of retained lipids promotes macrophage recruitment and foam-cell formation within the arterial intima. We therefore hypothesize that oxidative modification of locally retained lipids may similarly promote macrophage recruitment, foam-cell formation, and tissue remodeling within the prostatic lumen.
Methods
Whole-mount prostate tissues were obtained from organ donors (n=5) and patients undergoing simple prostatectomy for BPH (n=6) at UT Southwestern Medical Center. Global protein oxidative stress was assessed using the OxyIHC kit, while lipid peroxidation was evaluated using 4-hydroxynonenal (4-HNE) immunohistochemistry. Epithelial 4-HNE staining intensity was quantified with ImageJ and group differences were assessed by an unpaired t-test in GraphPad Prism. 7-ketocholesterol (7-KC), a product of cholesterol oxidation, and CD68+ macrophages were evaluated by immunofluorescence microscopy. Spatial localization of oxidative markers and CD68+ macrophages was evaluated in both donor and BPH prostate tissues.
Results
Quantitative analysis demonstrated significantly increased epithelial 4-HNE staining intensity in BPH compared with donor prostate tissue (p0.001). In contrast, OxyIHC revealed no apparent differences in global protein oxidative stress between donor and BPH tissues. Immunofluorescence demonstrated 7-KC immunoreactivity in both donor and BPH tissues. In one obstructed BPH specimen, intraluminal accumulation of 4-HNE, 7-KC, and CD68+ macrophages was observed, consistent with a localized oxidative microenvironment; however, this pattern was not found in the remaining specimens.
Conclusion
These findings support preferential epithelial lipid peroxidation as a feature of BPH despite no apparent increase in global protein oxidative stress likely due to differences in the sensitivity of these techniques. The intraluminal accumulation of oxidized lipids and CD68+ macrophages in an obstructed BPH specimen, but not in specimens without ductal obstruction, raises the possibility that localized oxidative-inflammatory microenvironments within the prostatic lumen may be associated with ductal obstruction. Together, these findings are consistent with a model in which selective lipid oxidation may contribute to an atherosclerosis-like inflammatory pathway in BPH. Further studies examining oxidized lipid-macrophage co-localization and lipidomic differences between donor and BPH prostate tissues will help determine which oxidized lipid species are associated with BPH and whether they serve primarily as markers of disease or actively contribute to macrophage recruitment, foam-cell formation, and BPH progression.