Abstract

Rationale:The current dogma of fibrosis pathogenesis is based on repetitive injuries of alveolar epithelial cells(AECs) leading to lung remodeling and epithelial stem cell exhaustion.Extensive apoptosis and senescence of AECs have been claimed, but the specific fate of IPF AECs remains unknown. Our aim was to clarify the epithelial cell fate in lung fibrosis and support the existence of partially apoptotic cells, that may contribute to fibrosis through their persistence in an injured and “undead” status.

Methods: IPF lungs were examined using immunohistochemistry. We assessed AECs using early apoptotic markers (cleaved caspase-3 and cleaved PARP) and late phase apoptosis markers (cleaved Lamin-a and a-Fodrin).The proliferation marker Ki67 and the senescent marker p16 was also used. We compared fibrotic lungs with normal lung area from lung cancer patients underwent surgery.

Results:We observed that the majority of epithelial cells in distal remodeled fibrotic airways that express early apoptosis markers, do not express late apoptosis markers, and are also Ki67 positive, implying that they represent cycling cells. Importantly, our results showed that those atypical epithelial areas are distinct from the senescent epithelial areas. On the contrary, epithelial cells in control lungs do not express apoptotic markers, neither stain positive for the senescent marker p16.

Conclusion:We showed for the first time that most of the epithelial cells supposed to be apoptotic, could be characterised as “undead cells”, as it was firstly described in Drosophilae. Our data indicate that AECs in IPF may fail to die and persist in a state of partial apoptosis.Targeting these newly identified cells maybe proved useful to control fibrogenesis.