Protective Effect of Cell Death and Immune Checkpoint Inhibitors in Experimentally Induced Endotoxin Sepsis in Animal Model

Sepsis is a multifactorial condition characterized by multiple organ failure and is often lethal in clinical settings.Effective therapeutics those target immune and inflammatory pathways in sepsis remained obscure.The present study aimed to evaluate the effect of cell death inhibitors (separate and combined) and the therapeutic potential of immune checkpoint inhibitors in endotoxin-induced sepsis.The lipopolysaccharide (LPS) was injected intra-peritoneally to both male and female BALB/c mice.Cell death inhibitors (i.e., Necrostatin-1, PJ34, Sibiriline) and immune checkpoint inhibitors (anti-PD1 and anti-CTLA4) were administered after 01 hour of LPS administration.The histopathological changes in tissue samples were observed by H&E staining, while TUNEL assay was performed to check apoptotic cells.qPCR was performed to assess the mRNA level of pro-inflammatory cytokines and tissue injury biomarkers were also evaluated.Current study results indicated that the gross pathological changes in kidney, spleen, and liver tissue induced by LPS was reduced by Nec-1 and PJ34 administration in mice.The levels of tissue injury markers (AST, ALT) were significantly (P≤0.05)higher in mice challenged with LPS in comparison to control mice.The expression levels of pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) were elevated in LPS challenged group compared to control mice which were decreased by cell death and immune checkpoint inhibitors.In conclusion, exogenous administration of cell death and immune checkpoint inhibitors showed protective effect in LPS-induced sepsis in mice by decreasing inflammatory markers and organ injury.