Pirinixic Acid Protects Against Hemorrhagic Shock by Regulating Neutrophil-Associated Key Genes.

BACKGROUND

The uncontrolled inflammatory cascade triggered by hemorrhagic shock (HS) can exacerbate tissue damage and organ dysfunction. Neutrophils, as the most abundant type of leukocytes, are key mediators of the innate immune response in the early stages of injury. There is a lack of suitable treatments targeting neutrophils in HS.

METHODS

We used machine learning algorithms to identify neutrophil-associated key genes in patients with HS and assessed the diagnostic efficacy of these genes. Weighted gene co-expression network analysis and consensus clustering analysis were performed based on the key genes to explore their role in HS. Finally, we predicted the binding of key genes to drug candidates using molecular docking and observed the effects of drug candidates and the expression of key genes in animals with HS.

RESULTS

We screened for key genes with good diagnostic efficacy (ARG1, F2RL1, MPP1, RHOG, UPP1) that activate JAK-STAT3 signaling and apoptotic signaling, leading to poor prognosis. Pirinixic acid screened by the Comparative Toxicogenomics Database has good affinity with key genes, and it can significantly restore the level of inflammatory factors and coagulation function in HS rats, protect the function of vital organs, and prolong the survival time. It was confirmed that pirinixic acid may improve neutrophil immunity disorders by acting on MPP1, RHOG, and F2RL1, and thus protect against HS.

CONCLUSIONS

The protective effect of pirinixic acid against HS-induced immune dysregulation is closely associated with the neutrophil genes MPP1, RHOG, and F2RL1.