Sally Yunsun Kim1,2 Qi Chen1, Sadia Sheikhuna2, Paulson Tseng1, Celia Diaz Nicieza1, Fiona J Culley1, Charlotte Dean1,
1National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, SW7 2AZ, United Kingdom.
2Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College London, London, SE1 9NH, United Kingdom.
Summary
Many safety and efficacy studies of novel therapeutics for lung diseases are conducted using in-vitro and in-vivo models. Precision-cut lung slices (PCLS) retain the complexity of the in-vivo microenvironment and can bridge the gap between in-vitro testing and in-vivo/clinical studies. We previously established the Acid Injury and Repair (AIR)-PCLS model to understand mechanisms of tissue repair; using this model we demonstrated that Wnt5a is a potential pro-repair drug that enhances the induction of alveolar type II epithelial/progenitor cells.
The aims of this study were to: (i) critically review the merits of PCLS in investigating cytotoxicity and efficacy of novel therapeutics, and (ii) investigate whether PCLS derived from aged lungs are a viable ex-vivo tool. PCLS were obtained from young (10-12 weeks-old) and aged (18 months-old) mice and were investigated for their use as platforms to investigate pro-repair capacity of potential therapeutics.
The use of PCLS for the investigation of novel therapeutics paves the way for an innovative advancement in preclinical respiratory research and drug development. We identified that there were limited number of studies that utilised PCLS as a tool to investigate inhalable therapeutics.
By comparing PCLS from young and aged lungs, we observed that aged PCLS exhibited key hallmarks of ageing, including increased type I collagen deposition compared to young PCLS (21.8% vs 8.5%, p=0.0001). Aged AIR-PCLS exhibited minimal increase in the percentage of proSP-C+ alveolar type II epithelial cells compared to young PCLS, which indicates reduced repair capacity.
In summary, PCLS is a physiologically relevant ex-vivo tool that enables comprehensive studies of cell viability, inflammatory responses, and drug responses. Aged PCLS retain the key hallmarks of ageing, which is significant as aging is a risk factor for many lung diseases. This study further supports the potential of incorporating PCLS, in particular aged PCLS, for the investigation of novel therapeutics for lung diseases.