The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. While anti-inflammatory treatment is not effective for IPF patients, researchers have found that damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we established organoid-based lung fibrosis model using mouse and human lung tissue to assess direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrated that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β played an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and identified potential therapeutic targets.
Yasunori Enomoto, Hiroaki Katsura, Takashi Fujimura, Akira Ogata, Saori Baba, Akira Yamaoka, Miho Kihara, Takaya Abe, Osamu Nishimura, Mitsutaka Kadota, Daisuke Hazama, Yugo Tanaka, Yoshimasa Maniwa, Tatsuya Nagano, Mitsuru Morimoto (2023) Autocrine TGF-beta-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis., Nature communications, Volume 14, Number 1, pp. 4956
Published in 2023 Aug 31 (Electronic publication in Aug. 31, 2023, midnight )
(Abstract) The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-beta plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-beta-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets.(MeSH Terms)