Asthma has reached epidemic proportions worldwide and typically starts early in life. It is a complex disease that can be both chronic and heterogeneous, its causes are multifactorial, including genetic, viral, obesity, and a wide arrange of environmental factors (i.e. cigarette smoke, pollution, or inhaled airborne antigen exposure).
Given its complex etiology, there are many ways to approach the development of a clinically relevant animal models. This article provides a high-level summary of the current literature to assist pulmonary researchers with the development and assessment of pre-clinical models of asthma.
Pre-clinical models are designed to replicate the clinical presentation of the disease under study. For asthma, this is a difficult task as multiple phenotypes have been identified. There are many factors to replicate, in terms of clinical symptoms, physiological responses to stimuli, environmental triggers, and genetic biomarkers1.
The principal characteristics of asthma include reversible airflow obstruction, airway hyperresponsiveness, airway inflammation, mucus hypersecretion and airway remodeling. These phenotypes can vary depending on the inflammatory profile, and if the disease presents in an acute form, as an airway hyperresponsiveness (AHR) reaction, or in a chronic form, leading to permanent changes to the structure and function of the lungs1.
Mullane and Williams (2003) describe the ideal animal model for asthma as follows:
Most animals do not naturally develop asthmatic disease (with the rare exception of cats and horses) and require human intervention to become susceptible to developing the disease5. Historically, guinea pigs were the most popular model, given they are easily sensitized and have natural AHR responses9. In the early 1990s murine models of asthma were developed and they rapidly became the most widely used pre-clinical model.8 BALB/c , C57BL/6 and A/J mice are the current preferred strains, with BALB/c mice being the most popular, as they are considered to be immunologically Th-2 biased1. Mice are ideal given they are convenient, have a lower cost, and a wide variety of transgenic models are available for study. Mice are largely responsible for our current understanding of the pathogenic mechanisms of asthma5.
Larger animals have also been used to study asthma such as cats, dogs, non-human primates, and even horses. Non-human primates in particular, perhaps unsurprisingly, demonstrate similar responses to allergen challenges observed in humans, with an early and late phase bronchoconstriction response and a similar increase in airway eosinophilia. However, as commonly seen with larger subjects, using primates is expensive, labour intensive, and it can take over 18 months to develop a sensitized model5.
Although no singular pre-clinical model will replicate clinical asthma perfectly, a variety of animal models can be used to assess specific aspects of the disease (Table 1).
Table 1: Comparison of small vs large animal subjects for pre-clinical assessment of asthma
There have been an array of allergens used to develop asthmatic models, such as ovalbumin (OVA), house dust mite (HDM Dermatophagoides pteronyssinus(Der p) or D. farinae (Der f)), fungi (Aspergillus fumigatus,Alternaria alternata), cockroach extracts, Ascaris antigens, cotton dust, ragweed and latex (Hevea brasiliensis). The allergen of choice depends on the condition to be replicated and can be used separately or in combination7. The most popular allergens used experimentally today are OVA and HDM, summarized in this document, based on their ability to produce a Th-2 mediated inflammatory response.
Clinical asthma has varied etiology, environmental triggers, and endotypes, making it challenging for animal models to mimic human disease. However, animal models play a critical role in our ability to understand the pathogenesis of disease and test therapeutic interventions prior to clinical testing.
Pre-clinical asthma models require validation and understanding of the physiological differences between the animal model and humans. A few notable considerations when developing and validating asthmatic murine models include: