The role of inflammatory mediators in the overactive and bladder pain syndromes

The Overactive Bladder (OAB) and Bladder Pain Syndrome (BPS) are debilitating disorders for which the pathophysiological mechanisms are poorly understood. Injury or dysfunction of the protective urothelial barrier layer, specifically the proteoglycan composition and number, has been proposed as the primary pathological characteristic of BPS. For OAB, the myogenic theory with dysfunction of the muscarinic receptors is the most reiterated hypothesis. For both over activity of the inflammatory response has been posited to play a major role in these diseases. We hypothesise that BPS and OAB are peripheral sensory disorders, with an increase in inflammatory mediators, such as cytokines and chemokines, which are capable of activating, either directly or indirectly, sensory nerve activity causing the disease. The aim of the PhD is to identify potential new therapeutic targets for the treatment of BPS and OAB. We used medium throughput quantitative gene expression analysis of 96 inflammation associated mediators to measure gene expression levels in BPS and OAB bladder biopsies and compared them to control samples. Then we created a novel animal model of disease by specific proteoglycan deglycosylation of the bladder mucosal barrier, using the bacterial enzymes Chondroitinase ABC and Heparanase III. These enzymes specifically remove the glycosaminoglycan side chains from the urothelial proteoglycan molecules. We tested role of the identified mediators in this animal model. In addition, in order to determine on which patients peripheral treatment strategies may work, we assessed the effect of local anaesthetics on patients with bladder pain. Gene expression analysis did not reveal a difference in inflammatory genes in the OAB versus control biopsies. However, several genes were upregulated in BPS versus control samples, from which two genes, FGF7 and CLL21 were correlated with patient clinical phenotypes for ICS/PI symptom and problem indices respectively. In order to determine which patients are likely to respond to treatment, we sought to characterise the bladder pain in BPS patients. Using urodynamics and local anaesthetics, we differentiated patients with peripherally mediated pain and patients with central sensitisation of their pain. Finally to determine the role of these mediators in bladder pain, we created an animal model of disease, which specifically replicates the human pathology: namely disruption in the barrier proteoglycan molecules. CCL21 led to an increase in painrelated behaviour, while FGF7 attenuated this behaviour, as measured by cystometry, spinal c-fos expression and mechanical withdrawal threshold examination. In conclusion, we have identified CCL21 and FGF7 as potential targets for the treatment of BPS. Manipulation of these ligands or their receptors may prove to be valuable previously unexploited targets for the treatment of BPS.

Nancy Spero: pain and politics, 1966-1976

The ten-year period that started with Nancy Spero’s War Series (1966-70) and ended with the completion of Torture of Women (1974-6) were of vital importance to the development of this key figure of feminist art. This was the moment when Spero turned her focus to politics, departing from a practice that was concerned with personal disaffection, instead focusing on profoundly social concerns. Essential to this evolution is a focus on pain. From the War Series through the Artaud Paintings (1970-71), Codex Artaud (1971-2), and Torture of Women, pain, both internal and external, was imagined in multiple forms. In Spero’s explorations of the theme, pain becomes metaphoric of the experience of women living under patriarchy, an amorphous but still profoundly disabling sensation that attacks both body and mind. This thesis explores Spero’s use of physical pain during moment of feminist art’s emergence, seeing it as a political metaphor for the way in which patriarchy invisibly controls and undermines women. Framed broadly by the question of art's relationship with politics during this turbulent period of anti-war and feminist activism, this thesis closely examines the way in which an analogy to pain figures the body in the work in complex terms, pursuing an ideological ambition through recourse to feeling.