Late Breaking Abstract - Loss of PTEN induces alveolar epithelial cell senescence resulting in lung fibrosis via activated NF-?B

Abstract

Introduction: Idiopathic pulmonary fibrosis(IPF) is an aging-related disease without effective treatment and underlying mechanisms of alveolar epithelial cell(AEC) senescence remain poorly understood. We aimed to explore whether activated PTEN/NF-κB pathway accelerated AEC senescence thus resulting in lung fibrosis. Methods: Aging markers (p16 and p21), senescence associated-β-gal(SA-β-gal) and activation of PTEN/NF-κB pathway were detected in lung tissues from IPF patients and normal lung tissues. They were also detected in senescent AECs (A549 and rat primary type 2 AEC), which induced by bleomycin. Then human embryonic lung fibroblast(HELF) was cultured with the supernatants of senescent AEC, in which several cytokines (IL-1, IL-6, IL-8 and MMP9) of senescence-associated secretory phenotype(SASP) were tested. Furthermore, gene knock down to PTEN and NF-κB and pharmacological inhibitor(BMS-345541) of NF-κB were applied in AEC. Results: We observed higher expressed p16, p21, SA-β-gal, activated NF-κB and reduced PTEN expression in IPF lung tissues and senescent AECs. And increased SASP cytokines in senescent supernatants and redundant collagen deposition in HELF were found. When PTEN was knocked down, NF-κB was activated, and increased aging markers in AEC and collagen deposition in HELF were observed. Interestingly, AEC aging was relieved by NF-κB inhibitor although PTEN was knock-down. As expected, aging and collagen deposition were rescued by NF-κB knockdown. Conclusions: This study supports that IPF is an aging-related disease, and loss of PTEN activates NF-κB to induce premature senescence of AEC and collagen deposition in fibroblast thus involving in pathogenesis of IPF.