Basic Urology Research Laboratory
Room 618, Basic Science Building
|J. Todd Purves, M.D., Ph.D.|
Assistant Professor of Urology and Pediatrics, Cell Biology and Anatomy
Office: Room 623C, Clinical Science Building
Administrative Assistant: Kelly Lee Lucas
Francis “Monty” Hughes, Jr., Ph.D.
The Innate Immune System of the Genitourinary Tract
Over the past two decades, our understanding of the bladder urothelium has changed considerably from its perceived role as a mere barrier to protect against noxious agents in the urine. Evidence suggests that it also serves as a sensory tissue that relays information to the underlying detrusor muscle and to the CNS via afferent nerves located in the muscle and adventitia as well as within the urothelium itself. As the front line between the urine and underlying tissue, it is also the interface where bacterial and other uropathogens will first be encountered and where the initiation of a host response takes place.
The mechanism by which uropathogens engage and then evade host defenses has been an area of intense study which has yielded impressive amounts of data over the past several years. One discovery that may provide the next generation of understanding is the discovery of the inflammasome by Jurg Tschopp in 2002. This remarkable entity is a supramolecular structure assembled by Nod-like receptors (or AIM2) in response to cells coming into contact with Pathogen Associated Molecular Patters (PAMPs) or Danger Associated Molecular Patterns (DAMPs). Most of the investigations on these structures have been done on antigen presenting cells of the immune system, e.g., macrophages. However, they have also been identified in epithelial cell types such as those lining the gut and lung. Our laboratory was the first to localize these to the urothelium and characterize their activity in several models of bladder inflammation (i.e. cystitis).
Our work has shown that inflammasomes trigger inflammation in a well-known model of sterile inflammation using chemotherapeutic agents. Moreover, it has also been suggested that inflammasomes mediate infectious cystitis as encountered in urinary tract infections. Finally, inflammasomes appear to be important in the inflammation and fibrosis demonstrated in men suffering from bladder outlet obstruction caused by benign prostatic hyperplasia (BPH). Currently, we are studying how to manipulate these important inflammatory modulators and with several clinical goals in mind. On one hand, increasing their activity may help enlist the innate immune system to fight urinary tract infections, rather than continuing to rely on antibiotics which are becoming less effective in the age of drug resistance. On the other hand, decreasing their sensitivity to pressure changes may help prevent lower urinary tract symptoms (LUTS) in men with BPH.
Anatomical Bladder Innervation Studies to Improve Botulinum Toxin Therapy for Urological Conditions
The practice of using botulinum toxin for treatment of urological pathologies such as neurogenic incontinence, overactive bladder and pelvic pain has seen widespread global usage since the first studies on detrusor sphincter dysynergia in the late 1980s. As the range of application widens, efforts have been made to optimize the administration of the agent, which is given as multiple cystoscopic injections directly into the bladder wall. Given that the toxin works at the terminal nerve endings of efferent and afferent nerve fibers, as well as at synapses between pre- and post-ganglionic fibers, we postulated that precisely locating these fibers would enable more efficient and efficacious delivery protocols. Our laboratory was the first to generate a high definition, three dimensional map of the human bladder nerves as they travel from the pelvic plexus to innervate the entire bladder. Refining these to discern different fiber types and pathways will allow us to create the ideal injection templates for the use of botulinum toxin therapy in the treatment of urological conditions.
Hughes, F.M., Vivar, N.P., Kennis, J.G., Pratt-Thomas, J.D., Lowe, D.W., Shaner, B.E., Nietert, P.J., Spruill, L.S., and Purves, J.T. “Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation.” Am J Physiol Renal Physiol. 306(3): F299-308, 2014.
Shunmugavel, A., Mushfiquddin, K., Hughes, F.M., Purves, J.T., Singh, A, and Singh, I. “S-Nitrosoglutathione protects the spinal bladder: Novel therapeutic approach to post-spinal cord injury bladder remodeling.” Neurourol Urodyn. 9999:1-8, 2014.
Hughes, F.M., #McKeithan, P., *Ellett, J., Armeson, K.E., Purves, J.T. “Simvastatin suppresses cyclophosphamide- induced changes in urodynamics and bladder inflammation.” Urology. 81(1): 209-214, 2013.
Hughes, F.M., Corn, A.G., Nimmich, A.R., Pratt-Thomas, J.D, Purves, J.T. “Cyclophosphamide induces an early wave of acrolein-independent apoptosis in the urothelium.” Adv Biosci Biotech. 4(8b):9-14, 2013.