Rationale

It is estimated that 45% of all deaths in the developed world are attributable to fibroproliferative disease (Gieseck et al., Nature Reviews 18:62-76,2018). Accordingly, this round table will have broad appeal and be of interest to LUT healthcare professionals including Urologists, Gynaecologists, Geriatricians, Physiotherapists and Nurses, as well as to Pure and Applied Scientists. Ample time will be allowed for attendee questions.

Marcus Drake (Urologist)—Pathological basis and clinical implications of LUT fibrosis.
Urine storage capacity is aided by the elastic extracellular matrix (ECM) composition of the bladder wall and active relaxation of detrusor smooth muscle in response to distension. Tissue injury and inflammation result in excessive ECM deposition and fibrosis, where intensity and duration of the insult correlate with the degree of matrix accumulation. This can lead to diminished bladder capacity, poor compliance and decreased bladder wall contractile function. However, there seems to be individual variation in the extent of fibrosis. Conditions associated with bladder fibrosis include neurogenic lower urinary tract dysfunction, outlet obstruction, chemical/radiation cystitis, and urinary tract infections. Their clinical implications will be addressed.

Anthony Kanai (Pharmacologist and Chair)—Emerging targets for the treatment of inflammation and fibrosis.
While there is an abundance of potential molecular targets for the treatment of fibrosis, the regulatory and feedback mechanisms are not completely understood, adding critical importance to new targets to be discussed: 1) Human relaxin-2 (hRLX2), through its action on relaxin receptor-1 (RXFP1) to induce tissue remodeling and smooth muscle relaxation; 2) Soluble guanylate cyclase (sGC), the receptor for nitric oxide that becomes inactivated due to oxidative stress resulting in decreased cGMP and antifibrotic activity; and 3) Angiotensin-2 receptor (AT2R). While the renin-angiotensin system is known for regulating systemic blood pressure, it also has a significant role in modulating tissue inflammation and fibrosis. Gender differences, pathological mechanisms of action and drugs to treat LUT fibrosis will be discussed.

Christopher Fry (Physiologist)—Paediatric bladder fibrosis.
Several congenital anomalies are associated with the developing LUT, ranging from bladder exstrophy or myelomeningocoele in both sexes, as well as in boys with posterior urethral valves. Although considerable advances have been made in surgical correction of these anomalies, a dysfunctional LUT persists in a significant number of patients and is associated with excessive deposition of fibrotic extracellular matrix. Key questions to be addressed are the impact of such fibrosis on bladder wall filling compliance and contractile function, as well as identification of important intracellular signalling pathways that drive fibrosis and may constitute drug targets as part of an antifibrosis strategy in this group of patients.

Adrian Wagg (Geriatrician)—LUT fibrosis in ageing.
Ageing is a multifactorial process leading gradually to cell and organ dysfunction. It is characterized by increased inflammation and uncontrolled fibrosis with excessive accumulation of ECM components and is a major risk factor for multiple diseases including idiopathic pulmonary fibrosis, chronic kidney disease and urinary bladder dysfunction. With progressive advances in healthcare, the human life expectancy has increased worldwide, increasing the incidence of age-associated diseases and comorbidities many of which are inflammatory and fibrotic in nature. Ageing in the bladder is associated with decreased compliance and reduced capacity, non-voiding contractions, impaired contractile function, decreased flow rate (in men) and decreased urethral tone (in women). Tissue fibrosis and urothelial alterations are the principal causes of bladder dysfunction during aging. The contribution of LUT fibrosis and how its effects might be mitigated will be addressed.

Speaker Affiliations

• Marcus Drake, MD/PhD, Professor, Surgery & Cancer, Hammersmith Hospital, Imperial College, London, UK.
• Anthony Kanai PhD, Professor, Medicine, Pharmacology & Chemical Biology, University of Pittsburgh, US.
• Christopher Fry, PhD, Professor of Physiology, Pharmacology & Neuroscience, University of Bristol, UK.
• Adrian Wagg, MD, Professor of Healthy Ageing, University of Alberta, Edmonton, Alberta, CA.