Modulation of pentraxin 3 by vinpocetine ameliorates lung Inflammation in murine model of allergic asthma exacerbated by lipopolysaccharide

This study investigates the pathological role of pentraxin 3 (PTX3) and evaluates the therapeutic efficacy of vinpocetine (VINP) in a murine mixed granulocytic asthma (MGA) model induced by co‑exposure to ovalbumin (OVA) and lipopolysaccharide (LPS). An MGA model was established by the co-stimulation of LPS and OVA to BALB/C mice. The airway resistance measurements, tissue staining, investigation of mRNA expression levels in tissues, and analysis of serum and bronchoalveolar lavage fluid were performed. In addition, in vitro experiments, cytokine and chemokine expression levels were measured in A549, lung epithelial cells, stimulated with human Tumor necrosis factor-alpha (TNF-α) and in HuT78, human T cells, stimulated with anti-CD3/CD28 antibodies. In particular, gene silencing of PTX3 was performed in A549 cells. Finally, PTX3 knockout mice were used to investigate the role of PTX3 in the MGA model. VINP treatment reduced airway hyperresponsiveness, inflammatory cell infiltration, bronchial and alveolar tissue damage, and serum level of OVA-specific immunoglobulin E. Furthermore, VINP suppressed the expression of cytokines and chemokines. In vitro studies demonstrated a mutual positive feedback loop between PTX3 and TNF-α. In A549 cells, human alveolar epithelial cells, silencing PTX3 downregulated the expression of TNF-α, interleukin-8, and MCP-1, mimicking the effects of VINP. Furthermore, PTX3 directly elevated the production of T helper 2 cells (Th2) cytokines in HuT78 cells, human T cells. VINP reduced the expression of Th2 cytokines. In vivo, PTX3 deficiency mitigated the pathology of MGA and eliminated the pharmacological benefits of VINP, suggesting that PTX3 is the therapeutic mediator of VINP. This study demonstrated that PTX3 plays a crucial role in an MGA model and that VINP mitigates MGA by downregulating PTX3 expression. Our results suggest that therapeutic strategies modulating PTX3 may be important for the treatment of MGA, and that VINP can be considered as a therapeutic candidate.