Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
Yasunori EnomotoHiroaki KatsuraTakashi FujimuraAkira OgataSaori BabaAkira YamaokaMiho KiharaTakaya AbeOsamu NishimuraMitsutaka KadotaDaisuke HazamaYugo TanakaYoshimasa ManiwaTatsuya NaganoMitsuru MorimotoPublished in: Nature communications (2023)
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-β plays 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 potential therapeutic targets.
Keyphrases
- idiopathic pulmonary fibrosis
- induced apoptosis
- dna damage
- cell cycle arrest
- oxidative stress
- transforming growth factor
- gene expression
- signaling pathway
- cell death
- endoplasmic reticulum stress
- cell proliferation
- epithelial mesenchymal transition
- risk assessment
- transcription factor
- human health
- mass spectrometry
- climate change
- single molecule
- extracellular matrix
- atomic force microscopy
- liver fibrosis