The anti-inflammatory effects of Fuzapladib in an endotoxemic porcine model

Abstract

Endotoxemia is a systemic inflammatory condition caused by lipopolysaccharide (LPS) stimulation, which produces inflammatory cytokines. Fuzapladib (FZP) inhibits the activation of adhesion molecules found on the surface of inflammatory cells, mitigating inflammation. In this study, we evaluated the therapeutic effects of fuzapladib on inflammatory cytokines and cardio-respiratory function using an LPS-induced endotoxemic porcine model. Fifteen pigs were separated into three groups: low-FZP (n=5), high-FZP (n=5), and control (n=5). Pigs were administered LPS under general anesthesia, and complete blood cell count, blood biochemistry, inflammatory cytokines, and cardio-respiratory function were evaluated. Statistical analysis was performed using a linear mixed-effects model and the Steel-Dwass test, with a significance threshold of P<0.05. During the 4 hr experimental period, one pig in the control group and two pigs in the low-FZP group died due to hypoxemia and hypotension. In the early acute changes following LPS administration, the high-FZP group maintained significantly higher arterial oxygen partial pressure and normal blood pressure compared to the control group. Although interleukin-6 levels increased in all groups during the experiment, they were significantly lower in the high-FZP group compared to the control group. Other parameters showed no clinically significant differences. In conclusion, while high-dose fuzapladib did not reduce organ damage in the porcine endotoxemia model, it suppressed interleukin-6 production, delayed the progression of deterioration, and contributed to a reduction in mortality during the observation period.

Keywords: cardio-respiratory function; endotoxemia; interleukin; lipopolysaccharide; pig.

Fig. 1.

Temporal changes in Interleukin (IL)-1β, IL-6, IL-10, and Tumor Necrosis Factor (TNF)-α following lipopolysaccharide (LPS) administration. The x-axis represents the time elapsed after LPS administration, while the y-axis shows the values of IL-1β, IL-6, IL-10, and TNF-α. In the box plot, the whiskers represent the range of the data, with the upper whisker showing the maximum value and the lower whisker showing the minimum value. The top edge of the box indicates the 75th percentile, while the bottom edge indicates the 25th percentile. The horizontal line within the box represents the median value. In the case of IL-6, the high-dose fuzapladib (FZP) group exhibited significantly lower values than the control group at 120 to 240 min post-LPS administration (*: P<0.05). For other cytokine results, please refer to Supplementary File 5.