Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are generally thought to result from the combined effects of prostate enlargement and age-related changes in bladder function. However, prostatic inflammation has recently and unexpectedly emerged as a powerful determinant of disease severity. Two large clinical studies of men with BPH/LUTS revealed prostate volume and histologic evidence of prostatic inflammation to be the most powerful predictors of symptom severity, disease progression and need for surgery. We postulate that inflammation contributes to development and progression of BPH/LUTS by at least three mechanisms: stimulating hyperplastic growth, producing vascular dysregulation, and activating nociceptive signaling with sensitization of pelvic afferents. During the previous cycle of funding, we identified inflammation-induced interleukin-1/IGF-1 signaling as a key activator of reactive hyperplasia associated with inflammation. In this proposal we focus on the neurovascular effects of prostatic inflammation. Epidemiologic studies have correlated BPH/LUTS with risk factors for neurovascular disease and systemic inflammation including autonomic hyperactivity, obesity, diabetes and the metabolic syndrome. Several human studies have shown diminished blood flow associated transition zone hyperplasia, suggesting vascular dysregulation and/or ischemia as a key feature of BPH. Changes in prostate innvervation have been suggested by studies of nerve density in normal and hyperplastic prostates. And, finally, pain has recently been identified as a remarkably frequent, albeit generally under-recognized symptom among men with BPH/LUTS. Remarkably, the neurovascular response of the prostate to inflammation has never been studied. To address this challenge we have assembled a multidisciplinary team with expertise in prostate biology, inflammation, neurobiology and vascular biology. We will work together to characterize the neurovascular anatomy of the mouse prostate, investigate neurovascular responses to acute and chronic inflammation and elucidate the connection between interleukin signaling and the neurovascular response. We expect these studies to reveal neurovascular changes in the prostate associated with inflammation and help identify plausible mechanisms by which inflammation contributes to development and progression of BPH/LUTS. Further, we expect these studies to identify mechanistic biomarkers for inflammation-induced neurovascular changes that can be used in translational studies to interrogate human BPH specimens and correlate inflammation-induced neurovascular changes with specific symptoms, clinical features of the condition and likelihood of progression.
Large clinical studies of men with benign prostatic hyperplasia BPH/LUTS revealed prostate volume and histologic evidence of prostatic inflammation to be the most powerful predictors of symptom severity, disease progression and need for surgery. The influence of prostate volume may be attributed to an effect on bladder outlet resistance, but the mechanism by which inflammation contributes to development and progression of BPH/LUTS is unclear. We postulate that inflammation stimulates produces changes in the prostate blood supply and innervation that contribute to development of voiding symptoms. We will investigate this postulate in a mouse model of prostate inflammation. We expect these studies to reveal neurovascular changes in the prostate associated with inflammation and help identify plausible mechanisms by which inflammation contributes to development and progression of BPH/LUTS. They are likely to provide new insights that will translate into entirely new treatment approaches for men with BPH and lower urinary tract symptoms.
|Lee, Sanghee; Yang, Guang; Xiang, William et al. (2016) Retrograde double-labeling demonstrates convergent afferent innervation of the prostate and bladder. Prostate 76:767-75|
|Lee, Sanghee; Yang, Guang; Bushman, Wade (2015) Prostatic inflammation induces urinary frequency in adult mice. PLoS One 10:e0116827|
|Wong, Letitia; Hutson, Paul R; Bushman, Wade (2015) Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis. Prostate 75:23-32|
|Wong, Letitia; Gipp, Jerry; Carr, Jason et al. (2014) Prostate angiogenesis in development and inflammation. Prostate 74:346-58|
|Boehm, Bayli J; Colopy, Sara A; Jerde, Travis J et al. (2012) Acute bacterial inflammation of the mouse prostate. Prostate 72:307-17|
|Bjorling, Dale E; Wang, Zun-Yi; Bushman, Wade (2011) Models of inflammation of the lower urinary tract. Neurourol Urodyn 30:673-82|
|McLaren, Ian D; Jerde, Travis J; Bushman, Wade (2011) Role of interleukins, IGF and stem cells in BPH. Differentiation 82:237-43|