Elsevier

Drug Discovery Today

Volume 16, Issues 21–22, November 2011, Pages 914-927
Drug Discovery Today

Review
Keynote
Harnessing opportunities in non-animal asthma research for a 21st-century science

https://doi.org/10.1016/j.drudis.2011.08.005Get rights and content

The incidence of asthma is on the increase and calls for research are growing, yet asthma is a disease that scientists are still trying to come to grips with. Asthma research has relied heavily on animal use; however, in light of increasingly robust in vitro and computational models and the need to more fully incorporate the ‘Three Rs’ principles of Replacement, Reduction and Refinement, is it time to reassess the asthma research paradigm? Progress in non-animal research techniques is reaching a level where commitment and integration are necessary. Many scientists believe that progress in this field rests on linking disciplines to make research directly translatable from the bench to the clinic; a ‘21st-century’ scientific approach to address age-old questions.

Introduction

Only two new classes of asthma drug have progressed from the laboratory to the clinic during the past 50 years despite considerable funding and effort [National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs); http://www.nc3rs.org.uk/news.asp?id51405]. In the meantime, some 300 million people worldwide currently suffer from asthma and it remains the most common chronic disease among children. Although most asthma-related deaths occur in low- and lower-middle income countries, asthma is a public health problem globally. Approximately one in every 250 deaths worldwide is asthma related, and the incidence continues to increase (WHO; http://www.who.int/mediacentre/factsheets/fs094/en/index.html).

During the past 10 years, the UK Medical Research Council (MRC) alone has provided £35 million in funding for basic research on asthma (MRC, personal communication). However, a recent call from NC3Rs for ‘new experimental models with improved scientific and clinical relevance and reduced reliance on the use of animals’ sheds light on the obstacles facing asthma research in the UK (NC3Rs; http://www.nc3rs.org.uk/page.asp?id51231). Recent European Union-funded projects under the Seventh Framework Programme for Research and Technology Development (FP7) have also sought to explore the asthma–environment link (Europa: Cordis; http://cordis.europa.eu). The Innovative Medicines Initiative (IMI), a European project aimed at bringing medicines more quickly to the market, was launched in 2009 and has injected €246 million into research, including asthma. It is hoped that a large patient cohort will enable validation of human biomarkers and development of diagnostic criteria for mechanistic and therapeutic trials (Europa press release; http://europa.eu/rapid/pressReleasesAction.do?reference5IP/09/802). The identification of this area as a bottleneck, along with the imbalance of progress and funding, signifies the need to reassess the way that asthma research is carried out and to realign its direction.

Asthma is characterised by airway inflammation, airway hyper-responsiveness (AHR, which is defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction, chronic eosinophilic inflammation, airway remodelling and episodic airway obstruction [1]. The response of atopic individuals is complex, involving an ordered interplay between mediators, cytokines and cell migrations throughout the respiratory tract, draining lymph nodes and blood. It is now clear that a wide range of environmental factors, superimposed on a genetic background, determine the occurrence and severity of asthma [2]. Although concerted international efforts of scientists and clinicians, the pathobiology of asthma is still relatively poorly understood [3].

Epidemiological studies can yield a great deal of information and clinical investigations are powerful tools; however, owing to ethical constraints and regulations surrounding clinical trials since the first mouse models were published in 1994, there has been a general reliance on animal models for asthma studies [3]. During this time, despite gleaning some information on the disease, progress has been slow in elucidating information on the causes, onset, persistence and treatments, owing in part to limitations associated with currently available models 3, 4. Despite asthma having originally been discovered as an inflammatory disease through human studies [5], artificially induced animal models of the disease have become increasingly prevalent, in particular murine models. Some investigators have described such models as ‘indispensable’ from a drug-screening standpoint [6]; whereas others have observed that animal models have intrinsic limitations [3].

The concept of ‘personalised medicine’ is especially relevant to a disease such as asthma, and the term ‘personalised research’ has been coined to demonstrate the need for basic research in asthma to reflect the variety of phenotypes that patients present. In many cases, only a reductionist approach is possible; however, complex behaviours of the larger system can be modelled computationally using systems biology tools. With this in mind, there are techniques outside of the mainstream asthma research field that have already shown great promise or that, with some targeted development, could be used to approach the asthma questions from a different angle. In this review, I analyse the current models used in asthma research and highlight the available components that could form part of a change in the way that asthma research is conducted.

Section snippets

The current climate: animal models

The species of animal most commonly used in asthma research include dogs 3, 6, sheep [7] and non-human primates (NHPs; principally rhesus and cynomolgus macaques) [8], as well as mice [9], rats [10], cats [11] and guinea pigs [12], with the most prevalent being the murine model. Mouse models have seen a dramatic rise in use over the past decade in an effort to probe the fundamental immunological causes of the disease and to identify and test novel therapeutic strategies [13]. However, in

Modelling without animals

In vitro studies are often cited as lacking the biological complexity of an in vivo system; yet it can also be said that animal models are a ‘black box’ of sorts that also do not permit a complete understanding of the complex mechanistic interactions within an animal, or the differences between humans and a model species. According to some researchers, the complex mechanisms underlying the genetics of sensitisation and pathophysiology necessitate in vivo studies. They regard the mouse model as

Concluding remarks

Unlike in regulatory testing, a common infrastructure for using 3Rs methods in basic research is rare. Notwithstanding achievements made to date in the treatment of asthma, the relevance of artificial animal models is considered to be overestimated in many cases, which could be contributing to the current disease research climate (i.e. sufficient research but insufficient progress). With animal research, some fundamental issues are often overlooked, such as species-dependent differences,

Acknowledgement

The author would like to thank Troy Seidle and Gill Langley for their reviews of this manuscript.

Gemma L. Buckland obtained her BSc (Hons) at King's College London in Immunology and Microbiology and her PhD from Imperial College London in T cell signalling. She currently works as a scientific consultant for the Humane Society International where her research interests include scientific advances in non-animal research methods for investigating infectious and immunologically based human diseases.

References (168)

  • M.L. Tang

    Airway remodelling in asthma: current understanding and implications for future therapies

    Pharmacol. Ther.

    (2006)
  • M. Karaman

    Effects of curcumin on lung histopathology and fungal burden in a mouse model of chronic asthma and oropharyngeal candidiasis

    Arch. Med. Res.

    (2011)
  • E. Huovinen

    Factors associated to lifestyle and risk of adult onset asthma

    Respir. Med.

    (2003)
  • S. Illi

    Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study

    Lancet

    (2006)
  • J.C. Celedon

    Exposure to cat allergen, maternal history of asthma, and wheezing in first 5 years of life

    Lancet

    (2002)
  • B. Schaub

    The many faces of the hygiene hypothesis

    J. Allergy Clin. Immunol.

    (2006)
  • P.G. Holt

    Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies

    J. Allergy Clin. Immunol.

    (2005)
  • M.J. Leckie

    Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response

    Lancet

    (2000)
  • V. Norris

    Effect of ivl745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma

    J. Allergy Clin. Immunol.

    (2005)
  • D.B. Tumas

    Anti-ige efficacy in murine asthma models is dependent on the method of allergen sensitization

    J. Allergy Clin. Immunol.

    (2001)
  • J.L. Wright et al.

    Animal models of copd: barriers, successes, and challenges

    Pulm. Pharmacol. Ther.

    (2008)
  • M.A. Sutherland

    Acute stress affects the physiology and behavior of allergic mice

    Physiol. Behav.

    (2009)
  • E.N. Meeusen

    Sheep as a model species for the study and treatment of human asthma and other respiratory diseases

    Drug Discov. Today

    (2009)
  • F.J. Kelly et al.

    Air pollution and airway disease

    Clin. Exp. Allergy

    (2011)
  • G.R. Zosky et al.

    Animal models of asthma

    Clin. Exp. Allergy

    (2007)
  • C.G. Persson

    Con: mice are not a good model of human airway disease

    Am. J. Respir. Crit. Care Med.

    (2002)
  • L.A. Laitinen

    Damage of the airway epithelium and bronchial reactivity in patients with asthma

    Am. Rev. Respir. Dis

    (1985)
  • T.K. Redman

    Pulmonary immunity to ragweed in a beagle dog model of allergic asthma

    Exp. Lung Res.

    (2001)
  • J.P. Capitanio

    Behavioral inhibition is associated with airway hyperresponsiveness but not atopy in a monkey model of asthma

    Psychosom. Med.

    (2011)
  • J.S. Dahlin

    IgE immune complexes stimulate an increase in lung mast cell progenitors in a mouse model of allergic airway inflammation

    PloS ONE

    (2011)
  • J. Liu

    PPARγ agonist rosiglitazone prevents perinatal nicotine exposure-induced asthma in rat offspring

    Am. J. Physiol. Lung Cell Mol. Physiol.

    (2011)
  • A. Gibbons

    The effect of liposome encapsulation on the pharmacokinetics of recombinant secretory leukocyte protease inhibitor (RSLPI) therapy after local delivery to a guinea pig asthma model

    Pharmaceut. Res.

    (2011)
  • S. Wenzel et al.

    The mouse trap: it still yields few answers in asthma

    Am. J. Respir. Crit. Care Med.

    (2006)
  • H. Sylvin

    The tryptase inhibitor apc-366 reduces the acute airway response to allergen in pigs sensitized to Ascaris suum

    Clin. Exp. Allergy

    (2002)
  • C.F. Ramsay

    Oral montelukast in acute asthma exacerbations: a randomised, double-blind, placebo-controlled trial

    Thorax

    (2011)
  • P. Mauser

    Effects of an antibody to interleukin-5 in a monkey model of asthma

    Am. J. Respir. Crit. Care Med.

    (1995)
  • T. Mosmann

    Two types of murine helper t cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins

    J. Immunol.

    (1986)
  • C. Taube

    Insights into the pathogenesis of asthma utilizing murine models

    Int. Arch. Allergy Immunol.

    (2004)
  • C. Deaton

    The role of oxidative stress in an equine model of human asthma

    Redox Report

    (2006)
  • I. Szelenyi

    Animal models of bronchial asthma

    Inflamm. Res.

    (2000)
  • G.R. Zosky

    The pattern of methacholine responsiveness in mice is dependent on antigen challenge dose

    Respir. Res.

    (2004)
  • M.N. Hylkema

    The strength of the ova-induced airway inflammation in rats is strain dependent

    Clin. Exp. Immunol.

    (2002)
  • N. Smith et al.

    Early- and late-phase bronchoconstriction, airway hyper-reactivity and cell influx into the lungs, after 5′-adenosine monophosphate inhalation: comparison with ovalbumin

    Clin. Exp. Allergy

    (2005)
  • J.C. Kips

    Murine models of asthma

    Eur. Respir. J.

    (2003)
  • K. Shinagawa et al.

    Mouse model of airway remodeling: strain differences

    Am. J. Respir. Crit. Care Med.

    (2003)
  • G. Rajagopalan

    Hla-dr polymorphism modulates response to house dust mites in a transgenic mouse model of airway inflammation

    Tissue Antigens

    (2011)
  • L. Vaickus

    Inbred and outbred mice have equivalent variability in a cockroach allergen-induced model of asthma

    Comp. Med.

    (2010)
  • K. Nemeth

    Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • J. Nikota

    Differential expression and function of breast regression protein 39 (brp-39) in murine models of subacute cigarette smoke exposure and allergic airway inflammation

    Respir. Res.

    (2011)
  • S.N.P. Kelada

    Strain-dependent genomic factors affect allergen-induced airway hyper-responsiveness in mice

    Am. J. Respir. Cell Mol. Biol.

    (2011)
  • Cited by (12)

    • Human-specific approaches to brain research for the 21st century: a South American perspective

      2018, Drug Discovery Today
      Citation Excerpt :

      Another core activity of the BioMed21 Collaboration is the funding of independent scientific reviews to explore the concepts of AOPs and human-specific models across a variety of disease areas. Published reviews are available for asthma [49], ALS [14], Alzheimer’s [14], autism [15], autoimmune diseases [50], cholestatic liver diseases [51] and tuberculosis [52] with similar reviews under development in the areas of cancer, cardiovascular disease, diabetes and virology. These reviews by independent experts in their respective fields have identified numerous animal models considered to be poorly predictive of the human condition, with recommendations for new research directions and opportunities utilizing the growing toolbox of 21st century, human-specific tools and technologies.

    • A look into the future of ALS research

      2016, Drug Discovery Today
      Citation Excerpt :

      However, in mice, overexpression of wild-type FUS induces motor neuron degeneration when significant amounts of protein accumulate in the cytoplasm [47]. Given their ability to recapitulate some key ALS features, animal models have been used to study ALS for almost two decades; however, the validity of animals as models for human diseases has been challenged and is generally debated [18,48–51] (http://dana.org/News/Details.aspx?id=42802). Often, the underlying mechanisms of action and resulting clinical manifestation found in animal models not only do not correlate with that in humans, but also guide researchers and resources along fruitless avenues.

    • Human Reconstituted Nasal Epithelium, a promising in vitro model to assess impacts of environmental complex mixtures

      2016, Toxicology in Vitro
      Citation Excerpt :

      Exposure effects should be confirmed by using mono-donor epithelia in order to consider inter-individual reactivity. Modern experimental European Union policy advocates finding in vitro alternatives to replace animal testing (Buckland, 2011). Human reconstituted epithelium models are currently the best representation of human respiratory tract physiology, and also the most robust for performing repeated exposures to atmospheric pollutants.

    • Considering a new paradigm for Alzheimer's disease research

      2014, Drug Discovery Today
      Citation Excerpt :

      An analysis of 76 highly cited studies on a range of animal species published in seven high-impact scientific journals found that only 37% accurately predicted human outcomes [14]. Despite sustained investment in animal models, disease-modifying therapies remain elusive for major illnesses such as Alzheimer's disease (AD) [15], stroke [16], motor neuron disease [17], Huntington's disease [18], asthma [19], sepsis [20] and inflammatory diseases [6]. The animal-model paradigm tends to discourage a critical appraisal of the differences between species and encourages a view that animal-based findings are generally applicable to humans [21].

    View all citing articles on Scopus

    Gemma L. Buckland obtained her BSc (Hons) at King's College London in Immunology and Microbiology and her PhD from Imperial College London in T cell signalling. She currently works as a scientific consultant for the Humane Society International where her research interests include scientific advances in non-animal research methods for investigating infectious and immunologically based human diseases.

    View full text