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. Author manuscript; available in PMC: 2021 May 12.
Published in final edited form as: Neurourol Urodyn. 2020 Jul;39(Suppl 3):S9–S15. doi: 10.1002/nau.24259

Are there relevant animal models to set research priorities in LUTD? ICI-RS 2019

Karl-Erik Andersson 1,2, Lori Birder 3,4, Christopher Chermansky 5, Russell Chess-Williams 6, Christopher Fry 7
PMCID: PMC8114418  NIHMSID: NIHMS1699944  PMID: 32662562

Abstract

Aim:

To discuss animal models of lower urinary tract disorders (LUTD) and their translational impact.

Methods:

Report of discussions based on presented literature-search based reviews relevant for the purpose.

Results:

Animal models can be used to investigate fundamental biological mechanisms, but also as tools to elucidate aspects of the pathogenesis of disease and to provide early evidence of any safety risk. Several different models may be required to obtain information that can have a translational impact. The term “translational research” covers not only the process of directly transferring knowledge from basic sciences to human trials to produce new drugs, devices, and treatment options for patients (T1 type translation) but also the implementation of early clinical research findings (phases I-III) into practice to improve care for patients (T2 type). Direct transfer of animal data to T2 is rarely possible, and the process often does not continue after the first trials in humans (phase I). It should be emphasized that many preclinical observations do not have (and do not need to have) immediate translational impact.

Conclusions:

No single animal model can mimic the complexity of the human disease. Still, animal models can be useful for gaining information on LUT function in humans, for elucidating pathophysiological mechanisms, and for the definition of targets for future drugs to treat LUT disorders.

Keywords: translational research

1 |. INTRODUCTION

The relevance of animal models for gaining information on lower urinary tract (LUT) function in humans and for the definition of targets for future drugs to treat LUT disorders (LUTD) is continuously being discussed. This article is a summary of a think-tank trying to answer the question “Are there relevant animal models to set research priorities in LUTD”. It is based on presented views on some currently used animal models and on how the information gained can be clinically useful. It also summarizes a general discussion focusing on the relevance and limitations of animal models of LUTD, on aspects of translational research, and on what we need to know further within the field.

2 |. WHY MOST PRECLINICAL ANIMAL MODELS, THOUGH USEFUL, ARE BOUND TO FAIL?

British statistician George Box1 was quoted as saying, “all models are wrong, but some are useful.” This phrase also applies to the use of animal models to understand human biology and the response to a treatment or intervention. The ancient Greeks were the first to use animals as models of human anatomy and physiology and these were purely observational. Later, animal research became more “experimental” rather than observational in nature. Choosing the most informative species for animal research comes with its own set of challenges which include financial feasibility as well as the specific biological characteristics of a particular species or strain. There is even a relatively new research area termed “gnotobiotics” which examines the influence of various microbiota on host physiology.2

The goal of most preclinical studies involving animals is to attempt to predict whether said interventions may have a benefit in human subjects. An exception is the US Food and Drug Administrations “Animal Rule,” which utilizes effective data in multiple species to license medical countermeasures against bioterrorism.3 However, no one animal model can be expected to capture all aspects of human physiology or a given disease. It is nearly impossible to overcome the disconnect between an animal model and human disease, though researchers have tried to come as close as possible to capture the pathological features of a disease in a preclinical animal model. While there has been much progress in designing and identifying new drug targets (such as computer-aided drug design),4 there has been a decline in success during clinical development.5 The reasons for the lack of success of animal models in predicting success in the clinic are many especially during target validation and preclinical proof-of-concept stage. First of all, diseases are incredibly complex (many are symptom-based) with a number of comorbidities along with incomplete knowledge of underlying mechanisms that can result in altered physiological function. Others cite a preponderance of studies with statistically significant results.6 The excessive success rate for preclinical studies may be due to reporting only positive findings which are thought to be the most valuable.

Animal research is valuable to gain insight into the pathogenesis of the disease, to establish nonclinical proof-of-concept evidence for any target of interest and efficacy and also to provide early evidence of any safety risk. A medicine or therapy is initially tested in vitro (using tissues and isolated organs) but legally and ethically must also be tested in a suitable animal model before clinical trials in humans can occur. A number of factors should be considered to improve translational value for animal models. These include the time course of treatment (in the clinic, treatment is usually started after the onset of symptoms), animal characteristics and background, age, sex, and health status of the animal and group size.

In terms of the future, there is a push toward developing animal models that are more sophisticated and clinically relevant and can be more predictive of the human condition.7 This may include using new genetic tools to develop “humanized” models (ie, transgenic animals that express human genes).8,9 An example of this approach uses the insertion of the gene encoding the human histocompatibility locus, HLA-B27 into rats, which increases the susceptibility to autoimmune conditions (similar to humans).10 Taken together, these new advances aim to keep animals in the forefront of translational research and of value toward the understanding of human health and disease.

3 |. ANIMAL MODELS TO BETTER STUDY MIXED LUT PATHOPHYSIOLOGIES

There are several well-established animal models for common LUT disorders. For example, intravesical acetic acid is used as a model for bladder overactivity,11 streptozotocin as a model for diabetic cystopathy,12 cyclophosphamide as a model for interstitial cystitis,13 and partial urethral obstruction as a model for bladder outlet obstruction.14 Most of these models evaluate single disease states, and many are injury models. Yet, many clinical conditions result from mixed pathophysiologies that do not result from an acute injury—and these mixed conditions are very common in the elderly. For example, benign prostatic hyperplasia and overactive bladder (OAB) coexist, stress urinary incontinence (SUI) and urgency urinary incontinence coexist as mixed urinary incontinence, and pelvic organ prolapse (POP) and SUI coexist.

Some investigators have been successful in producing animal models that address mixed LUT pathophysiologies. Jiang et al15 produced a rat model of SUI, with persistently low leak point pressures, using vaginal distention to produce urethral hypermobility and pudendal nerve crush to produce an intrinsic sphincteric deficiency. Takaoka et al16 produced a rat model of both detrusor overactivity and impaired bladder contractility (DOIC) using with bilateral crush of the pelvic nerve proximal to the major pelvic ganglion. Both of these models use acute injuries; however, the pathophysiologies of both clinical SUI and DOIC result from processes that are chronic. Genetic mouse models have recently been used to study LUT dysfunction. Couri et al17 used female lysyl oxidase-like 1 knockout mice, which have a genetic predisposition for abnormal elastin repair, to study both POP and SUI that results in 3 months postpartum. The prolapse worsened as the mice aged, paralleling what is seen clinically with POP. Wu et al18 used FVB-db mice, which have a mutation in the leptin receptor that produces severe insulin resistance and hyperglycemia, to study diabetic bladder dysfunction. They found that these mice had increased bladder capacities, increased voided volumes, and DO at both 12 and 24 weeks. Compared to the streptozotocin model of diabetes that results in detrusor underactivity, the FVB-db mouse model of diabetic bladder dysfunction demonstrates the more commonly seen condition in type 2 diabetic patients of bladder overactivity and impaired contractility, a mixed LUT pathophysiology.

Since so much clinical LUT dysfunction is seen in the aging population, and with so much LUT dysfunction involving mixed pathophysiologies, models need to be developed that better reflect these mixed conditions in aged animals. These conditions are too often studied in young animals. For example, the LUT dysfunction seen in young ovariectomized animals does not correlate with the changes seen in older, postmenopausal women. Thus, combining genetic and injury models in aging animals would correlate better in the investigation of LUT dysfunction seen in older patients.

4 |. CAN ANIMAL MODELS OF PSYCHOLOGICAL STRESS AND BLADDER FUNCTION REFLECT HUMAN CONDITIONS?

A bidirectional relationship exists between psychological stress and bladder function. It is well-established that bladder dysfunction, particularly incontinence, can cause significant distress to patients, while on the contrary, recent studies indicate that anxiety can influence the progression of bladder disease or even be responsible for inducing bladder dysfunction. This has been clearly demonstrated in the studies of Bradley et al,19 who observed female military veterans returning from active duty in Afghanistan and Iraq. In these subjects, the anxiety level was a strong predictor for the new development of OAB, while recovery for those with baseline OAB was also dependent on the level of anxiety and stress. Thus, stress has been shown to not only influence the progression of bladder dysfunction but also been implicated as a cause of urinary problems for subjects with high levels of anxiety.

A number of other studies related to stress and bladder dysfunction confirm this causative role of psychological stress in bladder dysfunction in patients,20,21 but the mechanisms involved in linking stress to physiological changes in the bladder are almost totally unknown and understanding them will require relevant animal models to be developed and fully characterized.

4.1 |. Animal models previously used to study bladder function

In general, a number of animal models of psychological stress have been developed to examine the different systems of the body, but few investigations of LUT function have been reported. To date, a number of rodent stress models have been employed:

  1. Water avoidance stress22: where animals are placed on an “island” surrounded by water or are placed in shallow water covering their feet.

  2. Social defeat23: animals are placed initially with an “aggressor” for a short period and then remain in the vicinity of the threat for a period of time afterward, separated by a transparent holed panel allowing smell and sight of the aggressor by the victim (Figure 1).

  3. Witness trauma24: in this model, a cohabiting mate of the social defeat victim observes the aggression and threat to its partner.

  4. Restraint stress25: animals are physically immobilized.

  5. Variate stress26: where a number of different stress inducers are used and change daily. These can include forced swim, electric shock, and restraint to induce stress.

  6. Spontaneously hypertensive rats27: these animals are spontaneously anxious and have an overactive bladder phenotype.

FIGURE 1.

FIGURE 1

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Victims of social defeat and witness mice have similar increases in glucocorticoid hormone levels

In most models, a period of stress (usually 1 hour) is induced each day for up to a month, with the most common duration of stress being 10 days. Female mice are most commonly used in the water avoidance model which causes an increase in urinary frequency, whereas social defeat requires victims and aggressors to be male.

Generally, results appear relatively consistent with an increase in urinary frequency with water avoidance stress using female rodents22 and urinary retention with social defeat stress where male rodents have to be studied.23 The difference is not surprising considering the gender differences in anatomy/physiology of the lower urinary tract and stress (sympathetic nervous system) increasing bladder outlet resistance in the male. Also, not surprisingly, the effects of stress may be related to the duration and intensity of the stress stimulus. Few studies have examined these factors, but Mingin et al28 noted increased urinary frequency in male mice following the intermittent social defeat, but urinary retention with a continuous stress paradigm.

Other surprising findings is that the stress inducer itself might be important. Unpublished studies (Chess-Williams R, Sellers DJ, McDermott C) have shown neurogenic responses to electrical field stimulation are increased in the victim of social defeat while witness trauma has no effect on these responses. This difference occurs despite similar increases in plasma corticosterone levels in the victim and witness, suggesting that several mechanisms may be involved in the bladder responses to stress, depending on the stressor initiating the response (Figure 1). This indicates a complex situation in these models, but such complexities probably reflect those in patients and suggest different treatment options may be required for different sources of stress-induced bladder dysfunction.

A further complicating factor is the recovery of bladder function from stress. Our initial studies using water avoidance stress show that the frequency of voiding returns to normal after a period of recovery. However, the normalization of micturition is related to changes in compliance rather than recovery and correction of bladder function (unpublished data).

The results in different models offer a range of tools to study stress on LUT function and depending on which aspect is to be investigated. Different results in different models should not be unexpected and may offer advantages when selecting a model for studying a particular condition. These basic concepts need to be confirmed in humans to identify the most clinically relevant findings, while the mechanistic pathways are dissected in experimental animal models.

The literature is consistent in supporting a causative link between psychological stress and bladder dysfunction in humans, but the animal models required to study the mechanisms involved in this link are varied. More information is required from human studies to enable the choice of model with the most relevant mechanisms to be identified. Which stressor, over what time period, best represents human conditions need to be identified but this will necessitate a greater understanding of the human situation. Only then can the relevant models be used to elevate our understanding of the physiology and pharmacology of these conditions and ultimately develop new treatments for patients.

5 |. HOW WELL DO ANIMAL MODELS INFORM US OF HUMAN PHYSIOLOGY AND PATHOPHYSIOLOGY?

Biological science research offers two broad motivations: to understand the fundamental properties of cells and tissues that allow us to understand the basic principles of how they function, and to provide a basis to understand pathophysiological changes. Both are essential activities although in some research environments the current fashion is to promote “translational science” which implies that rigorous understanding of the basics is of less strategic importance. Research in the LUT is no exception with an important motivation to understand the basis of benign and malignant pathologies.

The development of animal models of benign LUT pathologies has a long history although it is less clear what breakthroughs there have been that translate to the alleviation of the causes or symptoms of such conditions. For example, much drug development has relied on observing side-effects when they were applied for different purposes29,30 or used for particular pathophysiology but only later were the actual mode(s) of action investigated.31 Perhaps the development of β3-agonists comes closest to an idealized approach for an agent that reduces OAB symptoms through detrusor smooth muscle relaxation,32 although even in this instance other targets are being identified.33

5.1 |. Benefits and disadvantages of animal and human models of LUT pathophysiology

Small mammalian animal models offer a number of advantages: the strains provided by suppliers are relatively homogeneous, they are relatively easy to handle and house, they can provide genetically modified models, and the exchange of data between laboratories is more reliable. However, there are disadvantages that can make translation to human conditions difficult: they can be phylogenetically and physiologically very different from humans; they demonstrate variable responses to potential therapeutics; their shorter natural life spans can make long-term (aging) studies difficult to interpret. Moreover, external pressures can hinder the use of small animals: social pressures, the complexity of gaining ethical approval and costs are rising to the extent that many academic institutions are unable or unwilling to provide facilities.

Large animal models have similar advantages and constraints. Homogeneous populations are available, but the costs and requirements for more extensive facilities mean that research is limited to far fewer centers.34 Moreover, ethical permission, when required, is even more difficult to obtain and can impose considerable delays to research programs. Many of these issues can be ameliorated for ex vivo/in vitro research by using tissues and organs obtained from abattoirs and this is increasingly is being utilized.35

The use of human tissue for in vitro research offers an alternative and several centers have developed extensive research programs. The advantages are that extrapolation of data to the human condition is not necessary and there can be a direct application to characterize pathologies. It also increases the opportunity for exchange between research scientists and academic clinicians that is often missed when animal work is undertaken. However, certain work cannot be undertaken, in particular, interventional in vivo investigations. Moreover, the tissue comes from subjects with potentially a wide range of comorbidities and demographic differences that makes the generation of homogeneous experimental groups more difficult.

5.2 |. The importance of basic research

At the outset, it is important to emphasize the value of fundamental investigative research that does not have immediate translational worth. The goals of such work must include the provision of a set of knowledge that can be used to provide the bedrock of more applied projects. Animal research can most effectively provide this knowledge as confounding factors can be more effectively eliminated. Unfortunately, many journals, especially those who were at the science/medical interface and even funding agencies, are increasingly only interested in laboratory research that has immediate translational value. This is an attitude that fails to understand the underpinning relevance of fundamental research per se and appreciate that not all science can and needs to, be immediately translated.

6 |. DISCUSSION

Animal models may be used for several purposes, including the investigation of fundamental biological mechanisms, but also as tools to elucidate aspects of the pathogenesis of the disease. This is vital if the fundamental causes of pathological conditions are to be understood. To achieve this, different models and/or different classes of animal models can be used. Which class or classes to use should depend on what question to answer and approaches should be hypothesis-driven. Models used should as closely as possible mimic the human condition; however, even if they only resemble the human condition, they may be used to study underlying mechanisms of function/dysfunction. Desirably the models should be predictive in some way: even if they do not resemble the human condition, they can have a predictive value from an adverse effect point of view. Once the fundamental characteristics of the different models are better understood, they can be used in testing agents or procedures that may eventually be of use in humans. Animal models always have limitations. For example, an unclear human phenotype (ex OAB) will prevent the development of appropriate animal models. Inter-species, interstrain, and gender differences may be significant in many pathologies. The impact of age has always to be considered.

The main problem is how to translate information obtained from animal models to the human situation. For many, the term translational research refers to the “bench-to-bedside” approach i.e. the process of directly transferring knowledge from basic sciences to the clinic (sometimes referred to as T1 type translation). Such direct transfer is rarely possible, and the process often does not continue after the first trials in humans (phase I). However, the term translational research also covers the implementation of clinical research findings (phases I-III) into practice to improve care for patients (T2 type translation). A clear distinction between these two definitions of translational research has been suggested.29 T1 translation was described as “the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans.” T2 type translation was defined as “the translation of results from clinical studies into everyday clinical practice and health decision making.” Referring to T1 and T2 by the same name—translational research—has become a source of some confusion since their goals, settings, study designs, and investigators differ. T1 research requires appropriately trained clinical scientists with a mastery of basic sciences and with access to laboratories and with cutting-edge technology. T2 research requires different research skills: mastery of disciplines such as clinical epidemiology and evidence synthesis, communication theory, behavioral science, public policy, financing, and organizational theory. It should be emphasized that many preclinical findings and observations do not have (and do not need to have) immediate translational impact but may still be of interest.

A proposal of the think-tank was that the use of human tissue should play an earlier and more prominent role in characterizing fundamental mechanisms to understand pathological processes. This has two immediate advantages to the stakeholders—laboratory scientists and academic clinicians. The clinician needs to formulate and explain the pathological problem in a way that is amenable to research. The laboratory scientist will appreciate better the goal of the work and so develop a more focused program. A research approach can be formulated with an example directed to an understanding of the cause of detrusor overactivity (DO):

  • Identify the pathological problem to be answered: not too broad (eg, what is DO?), but relevant to the wider pathology (eg, do spontaneous contractions contribute to DO?).

  • Identify research objectives and specific outcomes using human tissue from patients with and without DO.

  • Identify animal models, preferably more than one to identify a more generic cause, that generate DO and investigate these possible causes. Thus, translational research using animal models becomes effective if they answer specific questions related to human pathophysiology.

  • Translate the outcomes and conclusions of animal research to the human condition if possible. This brings the work full circle as the laboratory scientist and academic clinician again has to engage.

A reinforcement of professional interaction between clinical observation and measurement, and laboratory research, utilizing appropriate animal and human models, is feasible in most academic settings and should provide a clearer approach to identify the nature of pathological conditions.

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