Species Comparison – Respiratory Assays
Approximately one-third of all respiratory abnormalities during human clinical trials can be attributed to unforeseen drug-mediated changes in airway resistance. Even guinea pigs, the most commonly used animal model of respiratory function, fail to replicate all human drug responses.1
The prediction of human bronchoconstriction could be vastly improved by performing an early species comparison study to explore the relevance of animal model to humans. At REPROCELL, our scientists can compare the effects of your test compounds on the constriction or relaxation of human airways (bronchi). We can also assess species differences in airway inflammation, using our , ex vivo, precision-cut lung slice (PCLS) and parenchymal explant models.
Species comparison models are a powerful tool in respiratory drug discovery, helping researchers bridge the gap between preclinical studies and human clinical trials. One of the biggest challenges in this field is selecting the right model system to translate preclinical findings into clinical success, whether it be studying airway constriction in asthma, bronchoconstriction in nonhuman primates, or epithelial dysfunction in fibrotic lungs. By comparing the effects of test compounds on airway constriction, relaxation, inflammation or fibrosis across both human and animal tissues, scientists can identify critical species differences early in development. This not only improves the predictability of human outcomes but also reduces costly late-stage failures. At REPROCELL, our ex vivo respiratory models, such as precision-cut lung slices (PCLS), parenchymal explants and engineered human lung models, enable direct side-by-side evaluation of airway responses, ensuring your drug candidates are both safe and effective before advancing to the clinic.
One example of the importance of species comparisons can be seen in Ellis & Fozard, 2002, in a study of bradykinin (BK), a peptide mediator involved in inflammation and respiratory function. BK has diverse effects on the airways, including bronchoconstriction, mucus secretion, cough, and oedema, primarily mediated by the B2 receptor subtype. These effects are often indirect, involving the activation of sensory nerves and the release of secondary mediators like prostanoids and nitric oxide. When comparing BK responses across species, notable differences have emerged—guinea pigs, for instance, exhibit airway responses to BK that most closely resemble those seen in human asthma. In contrast, other species such as mice, rats, and sheep show varying degrees of similarity, underlining the need for thoughtful model selection in preclinical research. Despite its relevance, the precise role of endogenous BK in human airway disease remains unclear, highlighting both the challenges and value of species comparison in understanding respiratory pharmacology.2
Similar insights have emerged from Seehase et al., 2011, using PCLS from nonhuman primates (NHPs) to investigate bronchoconstriction. By exposing lung slices from common marmosets, cynomolgus macaques, rhesus macaques, and Anubis baboons to a panel of bronchoconstrictors—including methacholine, histamine, leukotriene D₄ (LTD₄), U46619, and endothelin-1—researchers identified strong, species-specific responses. While all NHPs responded to methacholine, histamine, U46619, and endothelin-1, only cynomolgus macaques and baboons reacted to LTD₄, a leukotriene relevant in human airway disorders. Serotonin, a bronchoconstrictor in rodents, was ineffective across all NHPs, further aligning NHPs with human physiology, but with clear differences in the sensitivity to spasmogens across species (see figure below). These findings underscore the utility of NHP models—particularly cynomolgus macaques and baboons—in replicating human airway mechanisms and advancing translational respiratory research; however, no NHP species can replicate all aspects of human airway biology.3
The above figure shows the EC50 values of key bronchoconstrictors in isolated airways and precision-cut lung slices of preclinical species, in comparison to responses in humans. The data presented is a composite of data from REPROCELL’s studies in human isolated bronchi and published data in humans and various animal species4,5,6.
Ex vivo models such as isolated bronchi, precision-cut lung slices (PCLS) and organotypic cultures provide unique opportunities to study diseases like idiopathic pulmonary fibrosis (IPF) in a physiologically relevant environment. These systems preserve the complex interplay between epithelial cells, fibroblasts, and the extracellular matrix, offering insights that are often lost in simpler in vitro assays. In recent research, PCLS derived from fibrotic lungs have been instrumental in evaluating the effects of antifibrotic drugs not only on fibroblast activity but also on epithelial repair mechanisms—an emerging area of interest in the search for more effective IPF treatments. By leveraging these sophisticated models, researchers can more accurately predict human responses, investigate drug mechanisms, and identify potential new therapeutic targets.
, Together, these studies demonstrate the crucial role of species comparisons and advanced , ex vivo, models in enhancing the predictability and relevance of respiratory drug discovery. From identifying species-specific responses to inflammatory mediators to replicating complex disease environments like fibrosis, the careful selection and application of model systems can dramatically influence research outcomes. At REPROCELL, our focus on human biology and commitment to using physiologically relevant models helps our partners make smarter, data-driven decisions earlier in the development process. By bridging the gap between bench and bedside, we accelerate the path to safer, more effective therapies for respiratory diseases.
Find out more about our respiratory models →
References
- Dennis J. Murphy, Respiratory safety pharmacology – Current practice and future directions, Regulatory Toxicology and Pharmacology, Volume 69, Issue 1, 2014, Pages 135-140, ISSN 0273-2300,
https://doi.org/10.1016/j.yrtph.2013.11.010. - Ellis, K. M., & Fozard, J. R. (2002). Species differences in bradykinin receptor‐mediated responses of the airways. Autonomic and Autacoid Pharmacology, 22(1), 3–16. https://doi.org/10.1046/j.1474-8673.2002.00230.x
- S. Seehase, M. Schlepütz, S. Switalla, K. Mätz-Rensing, F. J. Kaup, M. Zöller, C. Schlumbohm, E. Fuchs, H.-D. Lauenstein, C. Winkler, A. R. Kuehl, S. Uhlig, A. Braun, K. Sewald, and C. Martin Journal of Applied Physiology 2011 111 : 3, 791-798. Bronchoconstriction in nonhuman primates: a species comparison
- Ressmeyer et al. (2006) Eur Resp J 28: 603-611
- S. Seehase, M. Schlepütz, S. Switalla, K. Mätz-Rensing, F. J. Kaup, M. Zöller, C. Schlumbohm, E. Fuchs, H.-D. Lauenstein, C. Winkler, A. R. Kuehl, S. Uhlig, A. Braun, K. Sewald, and C. Martin Journal of Applied Physiology 2011 111:3, 791-798. Bronchoconstriction in nonhuman primates: a species comparison
- Downes et al. (1986) J Pharmacol Exp Ther 237: 214-219