PGC-1α agonist ZLN005 ameliorates OVA-induced asthma in BALB/c mice through modulating the NF-κB–p65/NLRP3 pathway

Articles in Press

Document Type : Original Article

Authors

Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui, China

Abstract

Objective(s): Asthma is a complex inflammatory disease of the lungs marked by increased infiltration of leukocytes into the airways, which restricts respiratory function. Proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) has been recognized as an essential immunomodulator and has the potential as a novel anti-inflammatory target in asthma. The current study aims to investigate the functions of PGC-1α in ovalbumin (OVA)-sensitized asthmatic mice and underlying mechanisms.
Materials and Methods: BALB/c mouse asthma model was induced by OVA in vivo. The therapeutic effects of PGC-1α agonist (ZLN005) on asthma were assessed by histological and biochemical analysis. In addition, we integrated real-time qPCR, western blotting, and immunofluorescence analysis to reveal the underlying mechanism.
Results: In the lung tissue of asthmatic mice, PGC-1α levels were down-regulated. Diff-Quik staining indicated that ZLN005 therapy on asthmatic mice reduced the number of inflammatory cells (eosinophilic granulocytes, neutrophils, lymphocytes, and mononuclear macrophages) in bronchoalveolar lavage fluid (BALF), ameliorated pathologic alterations in lung tissues. ZLN005 alleviated airway structure and inflammation, as well as down-regulating the serum immunoglobulin E (IgE), OVA-specific IgE, and T-helper 2 (Th2) cytokines (interleukin (IL)-4, IL-5, and IL-13) expression. Mechanistically, the results showed that ZLN005, through the NF-κB-p65 axis, prominently inhibited the activation of the NLRP3 inflammasome and reduced the levels of the NLRP3 downstream targets IL-1β and IL-18.
Conclusion: PGC-1α agonist (ZLN005) regulated lung inflammation in asthmatic mice by inhibiting the NF-κB-p65/NLRP3 signaling pathway, supporting that ZLN005 may be a candidate for future asthma treatment.

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Main Subjects

References

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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 27 January 2025

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