Department of Physiology, Augusta University, 1120 15th Street, Augusta, GA, USA.
Department of Pharmacology, Faculty of Medical Science, University of Campinas (UNICAMP), Campinas, Brazil.
Pharmacol Rep. 2020 Feb;72(1):179-187. doi: 10.1007/s43440-019-00010-3. Epub 2020 Jan 8.
Benign prostatic hyperplasia (BPH) is associated with obesity and prostatic inflammation. The present study investigated the participation of toll-like receptor 9 (TLR9) in obesity-induced BPH, focusing on metabolic impairments, damage-associated molecular patterns (DAMP) levels and prostatic oxidative stress generation.
C57BL/6 (WT) and TLR9 mutant male mice were fed with regular or high-fat diet for 12 weeks. Metabolic profile, functional protocols, reactive-oxygen species (ROS) generation, prostatic histological analysis and DAMP levels were analyzed. Western blotting for prostatic TLR9 signaling pathway was also performed.
BPH in WT obese animals was characterized by increased prostate weight, smooth muscle hypercontractility and prostatic epithelial hyperplasia. Higher epididymal fat weight and prostatic ROS generation along with increased fasting glucose, triglyceride and circulating DAMP levels were also observed in WT obese group. Conversely, TLR9 mutant obese animals exhibited lower epididymal fat weight, fasting glucose and triglyceride levels associated with reduced prostate hypercontractility, prostatic ROS and circulating DAMP levels. However, TLR9 mutant obese mice were not protected from obesity-associated prostatic overgrowth and epithelial hyperplasia. Interestingly, TLR9 mutant lean mice exhibited augmented fasting glucose and prostatic ROS levels compared with WT lean mice. Despite increased prostatic expression of TLR9 in WT obese mice, no differences were seen in MyD88 expression between groups.
Improved obesity-induced BPH-related prostatic smooth muscle hypercontractility in TLR9 obese mice may be associated with amelioration in the metabolic profile, ROS and DAMP generation. Therefore, TLR9 could be a valuable target to improve obesity-associated metabolic disorders and prostate smooth muscle hypercontractility in BPH.
良性前列腺增生（BPH）与肥胖和前列腺炎症有关。本研究探讨了 Toll 样受体 9（TLR9）在肥胖引起的 BPH 中的作用，重点关注代谢损伤、损伤相关分子模式（DAMP）水平和前列腺氧化应激的产生。
C57BL/6（WT）和 TLR9 突变雄性小鼠分别用普通或高脂肪饮食喂养 12 周。分析代谢特征、功能方案、活性氧（ROS）生成、前列腺组织学分析和 DAMP 水平。还进行了前列腺 TLR9 信号通路的 Western 印迹分析。
WT 肥胖动物的 BPH 表现为前列腺重量增加、平滑肌过度收缩和前列腺上皮细胞增生。WT 肥胖组还观察到附睾脂肪重量增加、前列腺 ROS 生成增加以及空腹血糖、甘油三酯和循环 DAMP 水平升高。相反，TLR9 突变肥胖动物的附睾脂肪重量、空腹血糖和甘油三酯水平较低，与前列腺过度收缩、前列腺 ROS 和循环 DAMP 水平降低有关。然而，TLR9 突变肥胖小鼠并未免受肥胖相关的前列腺过度生长和上皮增生的影响。有趣的是，与 WT 瘦小鼠相比，TLR9 突变瘦小鼠的空腹血糖和前列腺 ROS 水平升高。尽管 WT 肥胖小鼠前列腺 TLR9 表达增加，但两组之间 MyD88 表达无差异。
TLR9 肥胖小鼠改善了肥胖引起的 BPH 相关前列腺平滑肌过度收缩，可能与代谢谱、ROS 和 DAMP 生成的改善有关。因此，TLR9 可能是改善肥胖相关代谢紊乱和 BPH 中前列腺平滑肌过度收缩的有价值靶点。
