Senescence of alveolar epithelial cells impacts initiation and chronic phases of murine fibrosing interstitial lung disease

Abstract

Fibrosing interstitial lung disease (ILD) develops due to the impaired reparative processes following lung tissue damage. Cellular senescence has been reported to contribute to the progression of fibrosis. However, the mechanisms by which these senescent cells initiate and/or drive the progression of lung tissue fibrosis are not yet fully understood. We demonstrated that p21WAF1/CIP1- and p16INK4A-pathway-dependent senescence in type 2 alveolar epithelial cells (AEC2) were both involved in the initiation and progression of lung fibrosis in murine bleomycin (BLM)-induced ILD. p21WAF1/CIP1-senescent AEC2 emerged rapidly, as early as 1 day after the intratracheal instillation of BLM. Their number subsequently increased and persisted until the later fibrosis phase. Very few p16INK4A-senescent AEC2 emerged upon the instillation of BLM, and their increase was slower and milder than that of p21WAF1/CIP1+ AEC2. AEC2 enriched with senescent cells sorted from BLM-ILD lungs expressed senescence-associated secretory phenotype (SASP)-related genes, including Il6, Serpin1, Tnfa, Ccl2, Tgfb, and Pdgfa, at the initiation and chronic phases of fibrosis, exhibiting distinct expression patterns of magnitude that were dependent on the disease phase. Ly6C+ inflammatory monocytes increased in the lungs immediately after the instillation of BLM and interstitial macrophages increased from day 3. The expression of Acta2 and Col1a1 was upregulated as early as day 1, indicating the activation of fibroblasts. We speculated that IL-6, plasminogen activator inhibitor-1 (PAI-1), and TGF-β contributed to the accumulation of senescent cells during the progression of fibrosis in an autocrine and paracrine manner. In addition, CCL2, produced in large amounts by senescent AEC2, may have induced the infiltration of Ly6C+ inflammatory monocytes in the early phase, and TGF-β and PDGFa from senescent AEC2 may contribute to the activation of fibroblasts in the very early phases. Our study indicated that senescent AEC2 plays a role in the pathogenesis of fibrosing ILD throughout the course of the disease and provides insights into its pathogenesis, which may lead to the development of new therapeutic methods targeting senescent cells or SASP molecules.

EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis

“…We and others have demonstrated that inhibition of EETs degradation reduces pulmonary fibrosis and COPD in mice [ 46 , 61 ], suggesting the ability of EETs to mitigate chronic age-related lung diseases. More and more studies have confirmed that AEC senescence is the initiating factor of various chronic lung diseases [ 62 , 63 ]. Cell senescence is a complex process that manifests as cell cycle arrest accompanied by changes in SASP gene expression and secretion [ 64 ].…”

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

“…This exposure may accelerate the growth of preneoplastic cells and subsequently boost the proliferation of cancer cells. Distinct types of proteases identified in the SASP include serine proteases and plasminogen activation pathway regulators, which are both associated with the development of cancer 176,177 . This family consists of the serine proteases, urokinase, and tissue‐type plasminogen activators (uPA and tPA, respectively), the uPA receptor (uPAR), and inhibitors of these serine proteases (PAI‐1 and ‐2) 178 .…”

Senescent AECⅡ and the implication for idiopathic pulmonary fibrosis treatment

“…In addition to this, incomplete replication of chromosome ends can lead to telomere shortening (Pineiro-Hermida et al, 2022). Recently, Pineiro-Hermida et al (2022) studied the telomeres of different cell types in the lung by controlling the TRF1 gene and confirmed that fibrosis only occurs when telomeres are disrupted in AECII, and telomere shortening can be compensated by the telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) (Pineiro-Hermida et al, 2022). Thus, preventing stress-induced telomere damage may prevent cells from entering replicative senescence and fibrosis.…”

“…However, it has also been demonstrated that TGF-β1 promotes lung fibrosis by inducing apoptosis in AECII. Recent studies have found that in bleomycin-induced lung fibrosis, the early production of TGF-β and platelet derived growth factor subunit A (PDGFA) by senescent AECII may directly promote fibroblast activation and collagen production, which in turn promotes fibrosis ( Yamada et al, 2022 ). In addition to the above signaling pathways, growth factors produced by different neighboring cells, intercellular contacts, immune cells, and the extracellular matrix also regulate the state of AECIIs ( Wu and Song, 2020 ).…”