Lung inflammation and interstitial fibrosis by targeted alveolar epithelial type I cell death

INTRODUCTION: The pathogenesis of chronic lung diseases is multifaceted with a major role of recurrent micro-injuries of the epithelium. While several reports clearly indicated a prominent role for surfactant-producing alveolar epithelial type 2 (AT2) cells, the contribution of gas exchange-permissive alveolar epithelial type 1 (AT1) cells has not been addressed yet. Here, we investigated whether repeated injury of AT1 cells leads to inflammation and interstitial fibrosis. METHODS: We chose an inducible model of AT1 cell depletion following local diphtheria toxin (DT) administration using an iDTR flox/flox (idTR(fl/fl)) X Aquaporin 5CRE (Aqp5(CRE)) transgenic mouse strain. RESULTS: We investigated repeated doses and intervals of DT to induce cell death of AT1 cells causing inflammation and interstitial fibrosis. We found that repeated DT administrations at 1ng in iDTR(fl/fl) X Aqp5(CRE) mice cause AT1 cell death leading to inflammation, increased tissue repair markers and interstitial pulmonary fibrosis. DISCUSSION: Together, we demonstrate that depletion of AT1 cells using repeated injury represents a novel approach to investigate chronic lung inflammatory diseases and to identify new therapeutic targets.