Philip M. Hanno, Jørgen Nordling, David R. Staskin, Alan J. Wein and Jean Jacques Wyndaele (eds.)Bladder Pain Syndrome – An Evolutionhttps://doi.org/10.1007/978-3-319-61449-6_6

6. Interstitial Cystitis: Animal Models

Tony Buffington^{1, 2}, Michael R. RuggieriSr.³ and David J. Klumpp⁴

(1)

Department of Medicine and Epidemiology, UC Davis School of Veterinary Medicine, Davis, CA, USA

(2)

The Ohio State University, Columbus, OH, USA

(3)

Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

(4)

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Tony BuffingtonClinical Professor, Emeritus Professor of Veterinary Clinical Sciences

Email: drbuffington@ucdavis.edu

In 1990, although the etiology and pathogenesis of the condition then referred to as “interstitial cystitis” (IC) was admitted to be largely or even completely unknown, the widely held implicit working assumptions held that it is a bladder disease. These assumptions implied that if we could discover and correct what was wrong with the bladder itself then we could cure the condition. These assumptions have proved to be largely off base. At that time, the previous suggestions that IC might have a primarily autoimmune or infectious etiology were largely abandoned. The autoimmune hypothesis still remains but has yet to be either been proven nor disproven conclusively.

Application of highly refined and exquisitely sensitive molecular techniques have essentially disproved the possibility of an infectious etiology. Because IC was assumed to be a bladder disease, investigations turned to “the relationship between IC and the properties of the surface of the bladder lumen.” Considerable evidence existed that the quality of the bladder surface mucin protects the bladder from bacterial colonization and from the irritative effects of noxious substances (e.g., H⁺, K⁺) in urine, so studies of mucin removal were conducted in healthy rabbits. In response to anecdotal reports that the antibiotic nitrofurantoin, commonly used to treat urinary tract infections, may act as a surface-active agent disrupting the bladder surface mucin and inducing IC, investigations attempted to use chronic nitrofurantoin administration to create an animal model of IC by studying both the acute and chronic effect of nitrofurantoin on the urinary bladder of rabbits. No such disruptive effect of nitrofurantoin on the bladder surface mucin was found. These investigations concluded that although experimental pathologies such as 1 h of bladder ischemia or overdistension and 1 week of partial bladder outlet obstruction, caused significant decreases in anti-adherence characteristics of the bladder mucosa, “whether these perturbations are transient or not remains the subject of further investigation.” The chapter concluded by proposing that the use of animal models to study isolated symptoms of IC would assist and greatly speed the process of investigation.

6.1 What Did We Get Right?

The authors of the chapter rightly summarized the work at the time of publication of the book, and presciently recognized that no one animal model of IC was likely to recapitulate all of the findings present in patients with the syndrome. Indeed, expectation that any animal model of a condition of unknown etiology and obscure pathogenesis can recapitulate all aspects of the clinical condition is a gross over expectation. The best that can be expected is to be able to create animal models with known etiologic and pathogenic mechanisms for specific symptoms of the condition and then to test whether these same mechanisms are involved in clinical cases.

The possibility was raised that “agents in the urine peculiar to patients with IC may initiate the pathogenic process.” Repeated infusion of urine from IC patients into the normal rabbit bladder has since been found to induce the classic cystoscopic appearance of interstitial cystitis [1, 2] and a number of abnormalities in the urine and urothelial cell structure and function have since been reported (see [3] for review).

6.2 Where Were We Off Base?

The mucin and glycosaminoglycan hypotheses ultimately were not supported [4–6]. Although bladder injuries certainly can be induced in animals, it remains mostly unknown if the resulting abnormalities represent models of cause, coincidence, or consequence of IC, limiting their relevance to IC in humans. That said, the recent reports of post-UTI chronic pain demonstrate that certain strains of E. coli have the capacity to induce pelvic pain behavior in mice that persists long after bacterial clearance, consistent with the prevalence of UTI history in IC patients [7]. Additionally, neonatal bladder inflammation can result in long-term visceral pain and altered responses of spinal neurons in adult rats [8, 9].

Two different strategies have been deployed to investigate IC in animals in the intervening years. One approach largely followed the recommendations of Chap. 14; the other was to investigate a (potentially) naturally occurring model of IC in domestic cats that was called “Feline Urologic Syndrome”.

In addition to continued studies of induced bladder injury, studies of the role(s) of environmental factors on the development of IC also have appeared. For example, increased voiding frequency was reported in corticotrophin releasing factor overexpressing mice [10], and both water avoidance stress [11, 12], and adverse early life experiences [13] have been found to result in irritative voiding signs in rodents.

Studies of the naturally occurring model of IC began with the same goal. Cats with sufficiently severe disease that their owners had elected euthanasia were obtained as donations, and then transported and housed in the vivarium of The Ohio State University and studied [14]. Three important initial observations were that many of the cats had variable combinations of signs of comorbid disorders (as is the case with humans with the syndrome), that these signs routinely resolved with housing in the enriched environment of the vivarium, and that they recurred in response to disruptions in the cats’ surroundings [15]. These findings resulted in the hypothesis that these cats, rather than having a bladder disease, might have a disease of the central nervous system that was afflicting the bladder and various other body systems (similar hypotheses have been investigated in humans [8, 14, 16]). We tested this hypothesis in a prospective observational study of “multimodal environmental modification” (MEMO) in client owned cats with the syndrome, and found that it led to significant reductions in signs referable to the bladder, as well as to other affected organs [17]. The MEMO approach subsequently has become the standard of care for cats with IC in veterinary medicine [18].

Like the induced bladder injury models, IC in cats also has limitations as a model of IC in humans. One is the seemingly different gender distribution between affected males and females of the two species. In cats, both genders are affected roughly equally, whereas early studies in humans suggested that 90% of patients were women [19]. Recent reports, however, suggest that the sex difference in humans may not be as large as originally thought [19, 20], if it exists at all [21, 22]. Additionally, affected cats are not easy to acquire without both veterinarian and owner cooperation, are more expensive to maintain in laboratory animal facilities than are rodents, are outbred, and lack many of the molecular tools available for rodents. Despite these limitations, studies of cats with IC have duplicated many results obtained in humans with IC, and even predicted some abnormalities that were subsequently found in humans with the syndrome [23, 24], in ways not currently possible in humans or induced animal models [25].

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