Development and Characterisation of a Murine Model System for Specific Pulmonary Epithelial Injury and its Repair Mechanism

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease with an unclear etiology and a low survival rate. The current limited treatment options and the challenges in modelling the disease reflect the lack of understanding of the precise mechanisms in this pathology.
Aberrant alveolar repair has been proposed to contribute to IPF development. Therefore, understanding the mechanisms of lung repair upon alveolar-specific injury may uncover IPF pathophysiology. To address this, we developed a mouse model utilising AAV9-DTR/DT system to achieve targeted alveolar cell ablation for studying alveolar repair under normal and stress conditions. As a comparison, AAV6.2-DTR/DT that target all lung epithelium was employed.
Longitudinal analysis of normal repair process was performed to observe the distinct phases of repair. Epithelial cells proliferation and differentiation occurred on days 4 and 8 post injury. On day 14 post injury, normal lung repair was complete as indicated by several parameters including weight of the mice, SP-D level, Ki67+ cell count, and gene expression profiles. Additionally, stress repair was recapitulated by exposing mice to cigarette smoke in combination with AAV-DTR/DT mediated injury. Smoking tends to exacerbate epithelial injury specifically in conditions of alveolar injury induced by AAV9-DTR/DT treatment.
Supported by the data from human primary small airways epithelial cells, our findings highlight the importance of AXL signalling in lung repair and the fibrotic response. The distinct temporal expression of pro-fibrotic genes and the interplay between AXL and TGF-ß pathways emphasise the potential of targeting AXL signalling for therapeutic intervention in IPF. Additionally, the intricate interactions between ligands and AXL underscores the necessity of balancing GAS6 and PROS1 to support normal lung repair.
In conclusions, our AAV-DTR/DT mouse model shows promise in investigating the etiology of IPF. Crucially, we uncover evidence that suggests AXL signalling is involved in lung repair mechanisms.

Date of Award	13 Nov 2024
Original language	English
Awarding Institution	University of Bath
Sponsors	Boehringer Ingelheim GmbH
Supervisor	Stephen Ward (Supervisor), Banafshe Larijani (Supervisor) & Kerstin Geillinger-Kästle (Supervisor)