How Is Asthma In Animals Similar To Asthma In Humans?

Animal Models of Asthma

Asthma has reached epidemic proportions worldwide and typically starts early in life. Information technology is a complex affliction that tin exist both chronic and heterogeneous, its causes are multifactorial, including genetic, viral, obesity, and a broad arrange of environmental factors (i.e. cigarette smoke, pollution, or inhaled airborne antigen exposure).

Given its circuitous etiology, there are many ways to approach the development of a clinically relevant animal models. This commodity provides a loftier-level summary of the current literature to assist pulmonary researchers with the development and assessment of pre-clinical models of asthma.

Developing an Ideal Asthma Model

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 chief characteristics of asthma include reversible airflow obstruction, airway hyperresponsiveness, airway inflammation, mucus hypersecretion and airway remodeling. These phenotypes tin vary depending on the inflammatory profile, and if the disease presents in an acute form, every bit an airway hyperresponsiveness (AHR) reaction, or in a chronic class, leading to permanent changes to the construction and role of the lungs¹.

Mullane and Williams (2003) describe the ideal fauna model for asthma every bit follows:

Genetics:Similar genetic basis to human disease, either naturally or engineered
Beefcake:Similar lung structure or a articulate understanding of the anatomical differences
Pathology: Like pathological response and underlining mechanisms involved with acute and chronic cases of disease
Validation:Similar endpoints are investigated pre-clinically that would exist investigated clinically such as AHR, Spirometry (FEV_ane), immunological profile (BAL), etc.
Response to intervention: Similar response to drugs or challenges of external stimuli (such as Methacholine) to what is observed clinically.

Current Pre-Clinical Asthma Models

Nearly animals do not naturally develop asthmatic illness (with the rare exception of cats and horses) and require human intervention to become susceptible to developing the affliction^v. 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 adult and they chop-chop became the most widely used pre-clinical model.⁸BALB/c , C57BL/6 and A/J mice are the current preferred strains, with BALB/c mice beingness the nearly popular, as they are considered to be immunologically Th-2 biased^one. Mice are ideal given they are user-friendly, accept a lower cost, and a wide multifariousness of transgenic models are available for study. Mice are largely responsible for our current understanding of the pathogenic mechanisms of asthma⁵.

Larger animals accept as well been used to study asthma such as cats, dogs, non-human primates, and even horses. Not-human being 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 unremarkably seen with larger subjects, using primates is expensive, labour intensive, and information technology tin can have over 18 months to develop a sensitized model⁵.

Although no singular pre-clinical model will replicate clinical asthma perfectly, a diverseness of beast models can exist used to assess specific aspects of the disease (Tabular array i).

Table one: Comparison of small vs big animal subjects for pre-clinical assessment of asthma

OVA and HDM Models

There have been an assortment of allergens used to develop asthmatic models, such as ovalbumin (OVA), house dust mite (HDM Dermatophagoides pteronyssinus(Der p) orD. farinae(Der f)), fungi (Aspergillus fumigatus,Alternaria alternata), cockroach extracts,Ascarisantigens, cotton grit, ragweed and latex (Hevea brasiliensis). The allergen of choice depends on the status 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 power to produce a Th-2 mediated inflammatory response.

Validation of Pre-Clinical Asthma Models

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 power to empathise the pathogenesis of disease and exam therapeutic interventions prior to clinical testing.

Pre-clinical asthma models require validation and understanding of the physiological differences between the fauna model and humans. A few notable considerations when developing and validating asthmatic murine models include:

Model development protocol– Clearly identifying the sensitization allergen, challenge antigen and specific murine strain, equally each cistron can have meaning influences on the endpoints of the resulting model⁹.
Acute vs. Chronic models-Acute and chronic models of asthma will have significant differences in their AHR response, inflammatory profile, and lung remodelling responses. It is important to evaluate both models when evaluating mechanisms of illness, pathogenesis, AHR and drug evolution⁴.
Structural and physiological-Mice lungs differ from humans in their beefcake and physiology. Structurally, the lungs differ in their branching and bronchiole to alveolar ratio, the type and location of cells within the lungs (i.due east. basal cells), less smooth muscle, and a lack of bronchial circulation^viii. It is important to go on in mind the differences and limitations when evaluating pre-clinical models.
Structure to part validation-AHR is ane of the main functional endpoints used to assess asthma and can exist influenced past a variety of factors such as the antigen used, airway remodeling, shine muscle cell hyperplasia, mucous department and blood flow distribution^v. In order to validate and assess the structural and functional changes in pre-clinical models a combination of techniques is required to develop a unified hypothesis cess including FOT, histology, BALF and computational modelling (if possible).