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  3. Carbon monoxide attenuates cellular senescence-mediated pulmonary fibrosis via modulating p53/PAI-1 pathway

Carbon monoxide attenuates cellular senescence-mediated pulmonary fibrosis via modulating p53/PAI-1 pathway

  • Eur J Pharmacol. 2024 Oct 5:980:176843. doi: 10.1016/j.ejphar.2024.176843.
Qianqian Wang 1,  Aohan Li 2,  Qian Li 2,  Jiaxin Li 3,  Qi Wang 2,  Siyuan Wu 2,  Jiaojiao Meng 2,  Changpeng Liu 2,  Dan Wang 4,  Yingqing Chen 5
Affiliations

Affiliations

  • 1 Engineering Technology Research Center for the Utilization of Functional Components of Organic Natural Products, Dalian University, Dalian, 116622, Liaoning, China; Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622, Liaoning, China.
  • 2 Engineering Technology Research Center for the Utilization of Functional Components of Organic Natural Products, Dalian University, Dalian, 116622, Liaoning, China.
  • 3 Engineering Technology Research Center for the Utilization of Functional Components of Organic Natural Products, Dalian University, Dalian, 116622, Liaoning, China; Case Statistics Office, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Harbin, 150011, China.
  • 4 Engineering Technology Research Center for the Utilization of Functional Components of Organic Natural Products, Dalian University, Dalian, 116622, Liaoning, China; Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622, Liaoning, China. Electronic address: wangdan1@dlu.edu.cn.
  • 5 Engineering Technology Research Center for the Utilization of Functional Components of Organic Natural Products, Dalian University, Dalian, 116622, Liaoning, China; Chronic Disease Research Center, Medical College, Dalian University, Dalian, 116622, Liaoning, China. Electronic address: chenyingqing@dlu.edu.cn.
PMID: 39068977 DOI: 10.1016/j.ejphar.2024.176843
Abstract

Purpose: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive condition often requiring lung transplantation. Accelerated senescence of type II alveolar epithelial cells (AECII) plays a crucial role in pulmonary fibrosis progression through the secretion of the senescence-associated secretory phenotype (SASP). Low-dose carbon monoxide (CO) possesses anti-inflammatory, anti-oxidative, and Anti-aging properties. This study aims to explore the preventive effects of CO-releasing molecule 2 (CORM2) in a bleomycin-induced pulmonary fibrosis model.

Methods: We established an pulmonary fibrosis model in C57BL/6J mice and evaluated the impact of CORM2 on fibrosis pathology using Masson's trichrome staining, fluorescence staining, and pulmonary function tests. Fibrogenic marker expression and SASP secretion in tissues and AECII cells were analyzed using qRT-PCR, Western blot, and ELISA assays both in vivo and in vitro. Additionally, we investigated DNA damage and cellular senescence through immunofluorescence and SA-β-gal staining.

Results: CORM2 showed a preventive effect on bleomycin-induced lung fibrosis by improving pulmonary function and reducing the expression of fibrosis-related genes, such as TGF-β, α-SMA, Collagen I/III. CORM2 decreased the DNA damage response by inhibiting γ-H2AX, p53, and p21. We identified PAI-1 as a new target gene that was downregulated by CORM2, and which was associated with cellular senescence and fibrosis. CORM2 effectively inhibited cellular senescence and delayed EMT occurrence in AECII cells.

Conclusion: Our study highlights the potential of CORM2 in preventing DNA damage-induced cellular senescence in bleomycin-induced pulmonary fibrosis through modulation of the p53/PAI-1 signaling pathway. These findings underscore the promising prospects of CORM2 in targeting cellular senescence and the p53/PAI-1 pathway as a potential preventive strategy for IPF.

Keywords

Carbon monoxide; Cellular senescence; DNA damage response; Plasminogen activator inhibitor 1; Pulmonary fibrosis.

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