MODELLING IDIOPATHIC LUNG FIBROSIS IN VITRO: A NOVEL STRATEGY FOR THE ASSESSMENT OF ANTI-FIBROTIC PHARMACEUTICALS

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5m
ICE Krakow

ICE Krakow

ul. Marii Konopnickiej 17 30-302 Kraków

Speaker

Simpson, Jessica (Durham University, Durham, UK ; Reprocell, Glasgow, UK)

Description

Idiopathic pulmonary fibrosis (IPF) is a degenerative and fatal disease, characterised by scarring of lung parenchyma and loss of respiratory function. Globally, this disease affects approximately three million people, and carries a typical life expectancy of 3-4 years at the point of diagnosis [1]. IPF is now considered to arise as a result of chronic damage to the alveolar epithelium, followed by pathological activation of underlying fibroblasts, excessive ECM deposition and remodelling, and the gradual stiffening of lung tissue [2]. The aetiology of IPF remains largely unknown, although several risk factors have been identified. Emerging data from the ongoing COVID-19 pandemic has highlighted a potential link between coronavirus infection and pulmonary fibrosis. Acute respiratory distress syndrome (ARDS), a form of respiratory failure, is often followed by pulmonary fibrosis. Early studies estimate 40% of patients presenting with COVID-19 pneumonia develop ARDS [3]. These patients are therefore at risk of developing pulmonary fibrosis as a long-term consequence of infection. Heavy reliance on in vivo animal models of IPF has impeded the discovery of effective therapeutic compounds, due to significant differences in animal and human pathophysiology. In human IPF patients, fibrosis is a chronic degenerative disease that occurs over a long period of time in response to a prolonged series of low-grade injuries. Most animal models however, represent an accelerated acute fibrotic response, linked to inflammation and in response to a single high-grade stimulus [2,4]. Such models therefore have limited pre-clinical success for screening therapeutic compounds. There remains a need for more representative, humanised models of IPF.

We have developed a novel in vitro construct that can incorporate both epithelial and interstitial fibroblast compartments to better recapitulate aspects of the alveolar epithelial tissue. These constructs utilise a porous, polystyrene scaffold membrane to support the growth of healthy and IPF-derived pulmonary fibroblasts, and thereby enable endogenous ECM deposition. Such models can be used for the assessment of anti-fibrotic compounds and their ability to modify ECM with the stomal compartment. Alveolar epithelial cells can also be seeded onto the underlying fibroblast compartment to form a more complex, full thickness model of the alveolar epithelium.

Quantification of endogenous collagen and fibronectin proteins within bioengineered constructs have shown an innate characteristic of IPF-derived fibroblasts to secrete and deposit greater concentrations of ECM fibres, relative to healthy lung fibroblasts. Incorporation of an overlying epithelial compartment has enabled the development of a more complex and more physiologically representative in vitro model of IPF. Such models can be treated with appropriate stimuli to mimic low grade chronic injuries to the alveolar epithelium which subsequently activate the underlying fibroblast compartment and further induces fibrosis.

These results highlight the potential for this novel bioengineered construct to be used for the assessment and effectiveness of anti-fibrotic compounds using in vitro assay analysis.

References
[1] Wuyts et al., Respiration. 99, 73-82 (2020)
[2] Wolters et al., Annu Rev Pathol. 9, 157-179 (2014)
[3] Wu, C. et al., JAMA Intern Med. 180(7), 1-11 (2020)
[4] Liu et al., Methods Mol Biol. 1627, 27-42 (2017)

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