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<p>Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with poor survival, which is characterized by abnormal accumulation of fibrotic tissue in the lung parenchyma. Transforming growth factor-β1 (TGF-β) is a central profibrotic mediator, but the related mechanism of the activation of latent TGF-β has not been conclusively elucidated. A comprehensive study of mRNAs in human IPF was conducted using GSE10667 microarray data from GEO database, and the expression of cartilage intermediate layer protein (CILP) was upregulated among end-stage pulmonary fibrosis (EPF) and acute pulmonary fibrosis (APF) as compared to non-fibrosis tissues. Furthermore, CILP has protein–protein interactions with TGF-β1 through PPI analysis. Therefore, we investigated the potential effects and mechanisms of CILP in pulmonary fibrosis in pulmonary fibroblasts and BLM-induced mouse model (Eight-week-old male C57BL/6 mice, 20–22&#xa0;g, purchased from the Experimental Animal Center of Guangzhou Medical University). In vitro, treatment with recombinant CILP (100&#xa0;ng/mL) significantly attenuated TGF-β1-induced upregulation of collagen type I (Col1a1,<i> p</i> &lt; 0.01) and α-smooth muscle actin (α-SMA,<i> p</i> &lt; 0.01) in primary mouse pulmonary fibroblasts. Mechanistically, CILP suppressed TGF-β1-mediated SMAD3 phosphorylation (p-SMAD3,<i> p</i> &lt; 0.001) and nuclear translocation, as confirmed by Western blotting and immunofluorescence. In the bleomycin (BLM)-induced mouse model of pulmonary fibrosis, intravenous administration of CILP (1&#xa0;μg/g body weight, administered every 2&#xa0;days for 4&#xa0;weeks) reduced lung collagen deposition (Masson staining) by 38% (<i>p</i> &lt; 0.01), lowered Ashcroft scores (from 5.8 ± 0.7 to 2.3 ± 0.4,<i> p</i> &lt; 0.001), and decreased lung hydroxyproline content (a marker of collagen accumulation) by 42% (<i>p</i> &lt; 0.01) compared to BLM-only controls. Clinically, serum CILP levels showed no significant difference between 17 idiopathic pulmonary fibrosis (IPF) patients and 17 non-fibrotic controls (3.2 ± 0.8&#xa0;ng/mL vs. 3.5 ± 0.9&#xa0;ng/mL, <i>p</i> &gt; 0.05), suggesting potential lung tissue-specific action of CILP with minimal systemic off-target risk. In conclusion, CILP inhibited TGF-β1-induced fibrosis via its negative feedback loop, and may act as a promising candidate for the precaution and treatment of IPF.</p>

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CILP attenuates pulmonary fibrosis through the TGF-β1/SMAD3 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月11日

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  • Hua Zou,
  • Jiale Dong,
  • Run Zhao,
  • Feng Liu,
  • Jingsong Cheng,
  • Xushan Li,
  • Chengshuo Fei,
  • Peng Li,
  • Chunlei Liu

摘要

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with poor survival, which is characterized by abnormal accumulation of fibrotic tissue in the lung parenchyma. Transforming growth factor-β1 (TGF-β) is a central profibrotic mediator, but the related mechanism of the activation of latent TGF-β has not been conclusively elucidated. A comprehensive study of mRNAs in human IPF was conducted using GSE10667 microarray data from GEO database, and the expression of cartilage intermediate layer protein (CILP) was upregulated among end-stage pulmonary fibrosis (EPF) and acute pulmonary fibrosis (APF) as compared to non-fibrosis tissues. Furthermore, CILP has protein–protein interactions with TGF-β1 through PPI analysis. Therefore, we investigated the potential effects and mechanisms of CILP in pulmonary fibrosis in pulmonary fibroblasts and BLM-induced mouse model (Eight-week-old male C57BL/6 mice, 20–22 g, purchased from the Experimental Animal Center of Guangzhou Medical University). In vitro, treatment with recombinant CILP (100 ng/mL) significantly attenuated TGF-β1-induced upregulation of collagen type I (Col1a1, p < 0.01) and α-smooth muscle actin (α-SMA, p < 0.01) in primary mouse pulmonary fibroblasts. Mechanistically, CILP suppressed TGF-β1-mediated SMAD3 phosphorylation (p-SMAD3, p < 0.001) and nuclear translocation, as confirmed by Western blotting and immunofluorescence. In the bleomycin (BLM)-induced mouse model of pulmonary fibrosis, intravenous administration of CILP (1 μg/g body weight, administered every 2 days for 4 weeks) reduced lung collagen deposition (Masson staining) by 38% (p < 0.01), lowered Ashcroft scores (from 5.8 ± 0.7 to 2.3 ± 0.4, p < 0.001), and decreased lung hydroxyproline content (a marker of collagen accumulation) by 42% (p < 0.01) compared to BLM-only controls. Clinically, serum CILP levels showed no significant difference between 17 idiopathic pulmonary fibrosis (IPF) patients and 17 non-fibrotic controls (3.2 ± 0.8 ng/mL vs. 3.5 ± 0.9 ng/mL, p > 0.05), suggesting potential lung tissue-specific action of CILP with minimal systemic off-target risk. In conclusion, CILP inhibited TGF-β1-induced fibrosis via its negative feedback loop, and may act as a promising candidate for the precaution and treatment of IPF.