Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with an unclear etiology and a high mortality. The unknown IPF pathophysiology reflects in the limited treatment options and the difficulties in modelling the disease.

Alveoli dysregulation has been suggested to influence IPF development. Thus, understanding the mechanism of lung repair upon alveolar injury might be the key to reveal IPF pathophysiology. To this end, we aim to develop a mouse model to achieve targeted alveolar cell ablation.

Cell ablation was achieved via Adeno Associated Virus serotype 9 (AAV9) expressing the human diphtheria toxin receptor (DTR), which has a specific tropism for alveolar cells. Time course experiment was performed to observe the distinct phases of repair. As a comparison, AAV6.2-DTR that target all lung epithelial cells, was utilized. Weight and SP-D levels were assessed. The cellular dynamics of the epithelial and immune cells were characterized by flow cytometry and single cell RNA sequencing. mRNA sequencing was performed to see the genetic changes during the repair.

Both AAV-groups lost weight and had increased SP-D concentration. The highest epithelial cells proliferation occurred on day 4 and the lowest on day 8 post injury. Distinct groups of profibrotic associated genes were serially and time-dependently upregulated. On day 14 post injury, the weight, SP?D, Ki67+ epithelial cells and gene profiles returned to near initial levels.

In conclusion, our AAV-DTR mouse model shows promise in investigating IPF etiology. The longitudinal analysis of selective epithelial injury revealed unique repair characteristics with a near complete lung repair at day 14 post injury.