2. Academic Validation
  3. Heparanase inhibition mitigates bleomycin-induced pulmonary fibrosis in mice by reducing M2 macrophage polarization

Heparanase inhibition mitigates bleomycin-induced pulmonary fibrosis in mice by reducing M2 macrophage polarization

  • Immunol Lett. 2025 Aug:274:107006. doi: 10.1016/j.imlet.2025.107006.
Long He 1,  Qianying Lv 2,  Jing Luo 1,  Yi-De Guo 1,  He Sun 3,  Ming Zong 4,  Lie-Ying Fan 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
  • 2 Department of Rheumatology, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 3 Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
  • 4 Department of Clinical Laboratory, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China. Electronic address: zongming@tongji.edu.cn.
  • 5 Department of Clinical Laboratory, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China. Electronic address: flieying@yeah.net.
PMID: 40180131 DOI: 10.1016/j.imlet.2025.107006
Abstract

Objective: This study investigates the involvement of heparanase in IPF pathogenesis and evaluates the therapeutic potential of heparanase inhibition.

Methods: Plasma heparanase levels were measured in IPF patients and healthy controls. Macrophage infiltration and heparanase expression in bronchoalveolar lavage fluid (BALF) were analyzed using immunofluorescence. Bleomycin (BLM)-induced pulmonary fibrosis mouse models were treated with the heparanase inhibitor OGT2115. Disease severity, macrophage polarization, and heparanase expression were assessed through histological staining, hydroxyproline content measurement, flow cytometry, immunofluorescence, Transmission Electron Microscopy and Western blot analysis.

Results: Elevated heparanase levels were found in the plasma of IPF patients and in macrophages from BALF. In BLM-induced mice, heparanase was predominantly expressed in M2 macrophages. OGT2115 treatment significantly reduced mortality, body weight loss, and fibrosis severity. Additionally, OGT2115 decreased M2 macrophage infiltration, attenuated lung fibrosis, and reduced Autophagy markers LC3 I/II and p62.

Conclusion: Heparanase plays a crucial role in modulating M2 macrophage polarization and the progression of IPF. Targeting heparanase with OGT2115 effectively ameliorates pulmonary fibrosis and represents a promising therapeutic strategy for IPF management.

Keywords

Autophagy; Heparanase; IPF; M2 macrophage; Pi3k/Akt.

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