AUTHOR=Carignon Sandra , De Moura Rodrigues Dorian , Gosset David , Culerier Elodie , Huot-Marchand Sarah , Savigny Florence , Kaya Eric , Quesniaux Valerie , Gombault Aurélie , Couillin Isabelle , Ryffel Bernhard , Le Bert Marc , Riteau Nicolas 

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

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1261483

DOI=10.3389/fimmu.2023.1261483

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>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.</p></sec><sec><title>Methods</title><p>We chose an inducible model of AT1 cell depletion following local diphtheria toxin (DT) administration using an iDTR flox/flox (idTR<sup>fl/fl</sup>) X Aquaporin 5CRE (Aqp5<sup>CRE</sup>) transgenic mouse strain.</p></sec><sec><title>Results</title><p>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<sup>fl/fl</sup> X Aqp5<sup>CRE</sup> mice cause AT1 cell death leading to inflammation, increased tissue repair markers and interstitial pulmonary fibrosis.</p></sec><sec><title>Discussion</title><p>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.</p></sec>