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Telomere shortening activates TGF-?/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis.

ABSTRACT: Telomere shortening is associated with idiopathic pulmonary fibrosis (IPF), a high-morbidity and high-mortality lung disease of unknown etiology. However, the underlying mechanisms remain largely unclear. In this study, wild-type (WT) mice with normal telomeres and generation 3 (G3) or G2 telomerase RNA component (TERC) knockout Terc^-^/- mice with short telomeres were treated with and without lipopolysaccharide (LPS) or bleomycin by intratracheal injection. We show that under LPS induction, G3 Terc^-^/- mice develop aggravated pulmonary fibrosis as indicated by significantly increased ?-SMA, collagen I and hydroxyproline content. Interestingly, TGF-?/Smads signaling is markedly activated in the lungs of G3 Terc^-^/- mice, as indicated by markedly elevated levels of phosphorylated Smad3 and TGF-?1, compared with those of WT mice. This TGF-?/Smads signaling activation is significantly increased in the lungs of LPS-treated G3 Terc^-^/- mice compared with those of LPS-treated WT or untreated G3 Terc^-^/- mice. A similar pattern of TGF-?/Smads signaling activation and the enhancing role of telomere shortening in pulmonary fibrosis are also confirmed in bleomycin-induced model. Moreover, LPS challenge produced more present cellular senescence, apoptosis and infiltration of innate immune cells, including macrophages and neutrophils in the lungs of G3 Terc^-^/- mice, compared with WT mice. To our knowledge, this is the first time to report telomere shortening activated TGF-?/Smads signaling in lungs. Our data suggest that telomere shortening cooperated with environment-induced lung injury accelerates the development of pulmonary fibrosis, and telomere shortening confers an inherent enhancing factor to the genesis of IPF through activation of TGF-?/Smads signaling.

SUBMITTER: Liu YY

PROVIDER: S-EPMC6289325 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Telomere shortening activates TGF-β/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis.

Liu Ying-Ying YY Shi Yao Y Liu Ya Y Pan Xing-Hua XH Zhang Ke-Xiong KX

Acta pharmacologica Sinica 20180620 11

Telomere shortening is associated with idiopathic pulmonary fibrosis (IPF), a high-morbidity and high-mortality lung disease of unknown etiology. However, the underlying mechanisms remain largely unclear. In this study, wild-type (WT) mice with normal telomeres and generation 3 (G3) or G2 telomerase RNA component (TERC) knockout Terc<sup>-</sup><sup>/-</sup> mice with short telomeres were treated with and without lipopolysaccharide (LPS) or bleomycin by intratracheal injection. We show that unde ...[more]

PMID: 29925920

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Project description:BackgroundBone marrow-derived fibrocytes reportedly play important roles in the pathogenesis of idiopathic pulmonary fibrosis. Pirfenidone is an anti-fibrotic agent; however, its effects on fibrocytes have not been investigated. The aim of this study was to investigate whether pirfenidone inhibits fibrocyte pool size in the lungs of bleomycin-treated mice.MethodsBleomycin (100 mg/kg) was infused with osmotic pumps into C57BL/6 mice, and pirfenidone (300 mg/kg/day) was orally administered daily for 2 wk. The lungs were removed, and single-cell suspensions were subjected to fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes, which were defined as CD45 and collagen-I double-positive cells. Immunohistochemistry was performed on the lung specimens to quantify fibrocytes. Chemokines in the lung digests were measured with enzyme-linked immunosorbent assay. The effect of pirfenidone on alveolar macrophages was evaluated with bronchoalveolar lavage (BAL). In a therapeutic setting, pirfenidone administration was initiated 10 days after bleomycin treatment. For chemotaxis assay, lung fibrocytes were isolated with immunomagnetic selection (CD45-positive mesenchymal cells) after culture and allowed to migrate toward chemokines in the presence or absence of pirfenidone. Moreover, the effect of pirfenidone on the expression of chemokine receptors on fibrocytes was evaluated.ResultsPirfenidone significantly ameliorated bleomycin-induced pulmonary fibrosis as assessed with quantitative histology and collagen measurement. Fibrocyte pool size in bleomycin-treated mice lungs was attenuated from 26.5% to 13.7% by pirfenidone on FACS analysis. This outcome was also observed in a therapeutic setting. Immunohistochemistry revealed that fibrocytes were significantly decreased by pirfenidone administration compared with those in bleomycin-treated mice (P = 0.0097). Increased chemokine (CC motif) ligand-2 (CCL2) and CCL12 production in bleomycin-treated mouse lungs was significantly attenuated by pirfenidone (P = 0.0003 and P < 0.0001, respectively). Pirfenidone also attenuated macrophage counts stimulated by bleomycin in BAL fluid. Fibrocyte migration toward CCL2 and chemokine (CC motif) receptor-2 expression on fibrocytes was significantly inhibited by pirfenidone in vitro.ConclusionsPirfenidone attenuated the fibrocyte pool size in bleomycin-treated mouse lungs via attenuation of CCL2 and CCL12 production in vivo, and fibrocyte migration was inhibited by pirfenidone in vitro. Fibrocyte inhibition is considered a mechanism of anti-fibrotic action of pirfenidone.

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Telomere shortening activates TGF-?/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis.

Publications

Telomere shortening activates TGF-β/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis.

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