The aim of this project is to reduce the use of mammalian models in inflammatory lung disease research by establishing zebrafish gill tissue as an alternative model to examine basic mechanisms and pathway biology of severe asthma.
Severe asthma is a disabling non-curable condition that can only be controlled by continuous administration of drugs. Traditional animal models, primarily rodents, have shed light on a number of basic mechanisms involved in severe asthma; however drugs developed against targets within these pathways have not translated to the clinic.
The pathophysiological mechanisms of severe asthma remain unclear. Much attention has focussed on the activation of TH1 and TH2 cells of the adaptive immune response, but it is now understood that there is need to study the interaction between innate immune cells and the epithelial lining of the respiratory system. Recent studies have suggested that environmental factors such as cigarette smoke, combined with viral infection may predispose the respiratory tissue to a higher incidence of asthma.
Although zebrafish do not have lungs, their gills serve the same functions and have a similar tissue structure with a single epithelial layer scattered with immune cells, and a layer of smooth muscle at the base of the lamella. Being exposed directly to the water, the gills can be easily targeted with any waterborne substance without having to use invasive procedures and can be sampled using small swabs in a longitudinal fashion.
Research details and methods
This project will translate approaches used to collect nasal tissue and fluids from human volunteers to gill tissue sampling in zebrafish. Swabs generated from bioengineered substrates will be used to non-invasively sample gill tissue and fluids to allow longitudinal studies in live fish following a short exposure to anaesthetic and analgesia. These studies to detect the presence of specific cells and soluble mediators will be combined with gene transcript analysis and live microscopy imaging to assess the behaviour of fluorescently-labelled immune cells under different conditions, including exposure to cigarette smoke and/or virus. Finally, data generated through these methods will be compared with human data to create hypotheses regarding the involvement of innate immune pathways in human respiratory disease.
Progatzky F et al. (2019). Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice and humans. Journal of Allergy and Clinical Immunology 144(1):342-345. doi: 10.1016/j.jaci.2019.04.003
Progatzky F et al. (2016). Mucosal inflammation at the respiratory interface: a zebrafish model. Am J Physiol Lung Cell Mol Physiol 310:L551–L561. doi: 10.1152/ajplung.00323.2015
- Further Funding: NC3Rs PhD Studentship, Live imaging of mucosal and vascular inflammation in zebrafish in response to a high cholesterol diet, September 2013, £90,000
- Further Funding: NC3Rs PhD Studentship, Refinement of hematopoietic cell transplantation using optical imaging in zebrafish, October 2016, £90,000