Overexpression of BPIFB4 Alleviates COPD Inflammatory Damage by Inhibiting M1 Macrophage Activation via the PI3K/AKT Pathway

  • Lung. 2025 Jun 16;203(1):69. doi: 10.1007/s00408-025-00824-4.
Lexin Xue  1  2 ,  Jingran Xu  3 ,  Hui Gong  4 ,  Zulipikaer Abudureheman  4 ,  Ayiguli ALimu  4 ,  Yun Chen  1 ,  Aifang Zheng  1 ,  Liang Gao  1 ,  Xiuqi Lu  2 ,  Chengxin Xie  1 ,  Li Li  5  6  7
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, First People's Hospital of Kashgar, Kashgar, Xinjiang, China.
  • 2. Department of Medicine, School of Medicine, Shihezi University, Shihezi, China.
  • 3. Department of Medical College, Xinjiang Medical University, Wulumuqi, China.
  • 4. Department of Clinical Research Center of Infectious Diseases (PulmonaryTuberculosis), First People's Hospital of Kashgar, Xinjiang, China.
  • 5. Department of Respiratory and Critical Care Medicine, First People's Hospital of Kashgar, Kashgar, Xinjiang, China. [email protected].
  • 6. Department of Clinical Research Center of Infectious Diseases (PulmonaryTuberculosis), First People's Hospital of Kashgar, Xinjiang, China. [email protected].
  • 7. Department of Medical College, Xinjiang Medical University, Wulumuqi, China. [email protected].
PMID: 40524026 DOI: 10.1007/s00408-025-00824-4
Abstract

Background: Macrophage polarization is essential for inflammatory regulation in COPD. The precise role of BPI Fold-Containing Family B Member 4 (BPIFB4) in regulating the inflammatory processes underlying COPD pathogenesis remains to be fully elucidated. This investigation seeks to clarify how BPIFB4 modulates macrophage polarization by activating the phosphoinositide 3-kinase (PI3K)-AKT1 signaling pathway, thereby influencing inflammatory progression in COPD.

Methods: In a COPD mouse model induced by cigarette smoke (CS) and lipopolysaccharide (LPS) and in cigarette smoke extract (CSE)-treated THP-1 cells, BPIFB4 was overexpressed or silenced. Bronchoalveolar lavage fluid, lung tissues, and serum were collected. qPCR and western blots assessed BPIFB4 and PI3K-AKT1 pathway expression in lung tissues and THP-1 cells. Flow cytometry evaluated M1/M2 macrophage polarization, and enzyme-linked immunosorbent assay (ELISA) measured related cytokine levels.

Results: The results demonstrated how BPIFB4 gene silencing resulted in more pronounced lung tissue and functional damage compared to BPIFB4 overexpression, alongside an elevated presence of M1 macrophages and associated pro-inflammatory factors. In contrast, BPIFB4 overexpression in both COPD mice and CSE-treated THP-1 cells significantly enhanced p-AKT1 and p-PI3K levels while reducing the number of M1 macrophages. In addition, inhibition of the PI3K-AKT1 pathway reversed these effects, resulting in a marked increase in M1 macrophages and their associated cytokines.

Conclusion: BPIFB4 overexpression alleviates M1 macrophage polarization by activating the PI3K-AKT1 pathway, thereby reducing lung tissue damage and dysfunction in COPD mice.

Keywords
BPIFB4; COPD; Macrophages; PI3K-AKT1; Polarization.
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