Back to the future: re-establishing guinea pigin vivoasthma models

Abstract

Research using animal models of asthma is currently dominated by mouse models. This has been driven by the comprehensive knowledge on inflammatory and immune reactions in mice, as well as tools to produce genetically modified mice. Many of the identified therapeutic targets influencing airway hyper-responsiveness and inflammation in mouse models, have however been disappointing when tested clinically in asthma. It is therefore a great need for new animal models that more closely resemble human asthma. The guinea pig has for decades been used in asthma research and a comprehensive table of different protocols for asthma models is presented. The studies have primarily been focused on the pharmacological aspects of the disease, where the guinea pig undoubtedly is superior to mice. Further reasons are the anatomical and physiological similarities between human and guinea pig airways compared with that of the mouse, especially with respect to airway branching, neurophysiology, pulmonary circulation and smooth muscle distribution, as well as mast cell localization and mediator secretion. Lack of reagents and specific molecular tools to study inflammatory and immunological reactions in the guinea pig has however greatly diminished its use in asthma research. The aim in this position paper is to review and summarize what we know about different aspects of the use of guinea pig in vivo models for asthma research. The associated aim is to highlight the unmet needs that have to be addressed in the future.

A new house dust mite–driven and mast cell–activated model of asthma in the guinea pig

“…Taken together, the purpose of this paper was to establish a new asthma model by the use of a species that physiologically, anatomically and pharmacologically has great similarities to humans 6 using a method for sensitization with a relevant allergen through respiratory mucosa that activates both the adaptive and the innate immunity in the airways. The study provides evidence that the used protocol generates several key features of asthma such as AIB, AHR, remodelling and recruitment of inflammatory cells (including mast cells) together with an increase of IL‐13.…”

“…However, for studying functional lung responses, mouse airway smooth muscle (ASM) has limitations in that it does not respond to several important agonists such as histamine and cysteinyl‐leukotrienes (Cys‐LTs) 6 and also do not show antigen‐induced bronchoconstriction (AIB) since very few mast cells are located in the peripheral parts of the mouse lung 7 . Moreover, murine airways also lack the bronchial circulation, mucus glands and the inhibitory innervation of their ASM that counteract the acute asthmatic attacks 6 . Therefore, to investigate the mechanisms that drive airway bronchoconstriction, there is a need for new improved pre‐clinical models that asthmatic features in humans.…”

“…Although the OVA‐driven model of asthma has been extensively applied in guinea pigs, OVA is not a trigger of human asthma 6 . Instead, current asthma models in animals are moving towards using more clinically relevant allergens, particularly those from the HDM, 12 as it has proven to induce a multifaceted immune response involving both the innate and adaptive arms of the immune system that do not appear in OVA models in mice.…”

Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

“…Guinea pigs are the standard pre-clinical model for studying cough (Adner et al, 2020;Bonvini et al, 2015;Lewis et al, 2007;Morice et al, 2007) as the main features of airway innervation are similar in guinea pigs (Mazzone and Undem, 2016) and humans (West et al, 2015), unlike mice or rats. Coughing in guinea pigs is mediated both by a subset of bronchopulmonary C-fibers and by a distinct mechanically-sensitive and acid-sensitive subtype of myelinated airway mechanoreceptors (Canning, 2006;Canning et al, 2014;Canning et al, 2004;Chou et al, 2018b;Mazzone et al, 2009;Mazzone and Undem, 2016).…”

Differential sensitivity of cinnamaldehyde-evoked calcium fluxes to ruthenium red in guinea pig and mouse trigeminal sensory neurons

“…Furthermore, knockout of TRPA1 has been shown to be protective in allergen-associated airway hyperreactivity [ 15 ]. The guinea pig ( Cavia porcellus ) is of particular interest for developing therapeutic targets for respiratory diseases as airway smooth muscle physiology, acute responses to allergen exposure, and ability to cough in response to inhaled irritant aerosols are more representative of human airways than those of rats or mice [ 16 , 17 ]. However, despite the many studies examining TRPA1 function in guinea pig tissues, the characterization of the channel itself remains incomplete.…”