Pelvic ganglia inflammation as a factor leading to organ crosstalk and coordinated development of bladder and erectile dysfunction following pelvic surgery. - Pelvic ganglia inflammation as a factor leading to organ crosstalk and coordinated development of bladder and erectile dysfunction following pelvic surgery. Abstract: Patients undergoing radical prostatectomy are at high risk of developing both bladder and erectile dysfunction, even when minimally nerve-sparing approaches are used to avoid direct damage to the urogenital organs and their neurovasculature. The goal of this proposal is to identify mechanisms that result in this coordinated development of bladder and erectile dysfunction (ED) following pelvic surgery. We recently reported that in rats, simple laparotomy results in ED 3 days after surgery, and is accompanied by systemic and also local inflammatory responses in penile cavernosal tissue, cavernous nerve (CN) and major pelvic ganglia (MPG). Interestingly, even though this surgical procedure avoids direct nerve injury, the profile of molecular changes in cavernosal tissue was strongly indicative of CN injury, suggesting that development of ED following nerve-sparing pelvic surgery may involve a systemic inflammatory response, resulting in indirect nerve injury. In preliminary data presented here, we demonstrate that in both rat models of minimally invasive pelvic surgery and direct CN injury, the development of ED is accompanied by significant changes in bladder function. Moreover, we also observed an inflammatory response at the level of the MPG, which innervates both cavernosal and bladder tissues. A pathological inflammatory response in the MPG may therefore mediate pelvic organ crosstalk leading to the coordinated development of bladder and erectile dysfunction. These observations have led us to the hypothesis that even following minimally invasive, nerve-sparing pelvic surgery that avoids direct damage to the urogenital organs, there is a pathological inflammatory response in the MPG that mediates pelvic organ crosstalk and coordinated development of bladder and erectile dysfunction. Furthermore, we hypothesize that modulating the inflammatory response will improve post-operative urogenital function outcomes. We will test these hypotheses with three Specific Aims. In Aim 1 we will utilize animal models to compare the impact of different levels of pelvic surgical trauma (naïve rats compared with those undergoing laparotomy, sham-CN injury, CN crush or CN transection) to correlate the time-course and severity of post-operative bladder and erectile dysfunction with the levels of the inflammatory response (systemically, in urogenital tissue, and in the CN and MPG). In Aim 2, we will investigate the impact of post-surgical inflammation on the MPG and determine the extent to which MPG molecular and structural remodeling provide a substrate for pelvic organ crosstalk leading to coordinated post-surgical development of bladder and erectile dysfunction. In Aim 3 we will use anti-inflammatory drugs to determine the role of the inflammatory response on the coordinated development of urogenital pathology and obtain pre-clinical rationale for the potential use of anti-inflammatories to improve post-operative urogenital function.
