Abstract
Hemorrhagic shock (HS) is a type of hypovolemic shock and is a leading cause of mortality worldwide. Enolase 1 (ENO1), a key enzyme in glycolysis, has been implicated in the pathogenesis of inflammatory disorders. We hypothesize that Kupffer cell (KC) ENO1 contributes to liver inflammation and that inhibiting ENO1 with ENOblock protects the liver from HS-induced injury. HS was induced in mice by lowering mean arterial pressure to 25 mmHg for 90 min, followed by fluid resuscitation. Twenty-four hours later, KCs were isolated. To mimic HS in vitro, KCs were isolated from healthy mice and exposed to hypoxia/reoxygenation (H/R). Hypoxic KCs were treated with ENOblock during reoxygenation, and cytokines (IL-1β, TNF-α, IL-6) were measured. In mice subjected to HS and treated with ENOblock, the liver was harvested. In KCs isolated from HS mice as well as in H/R exposed KCs, ENO1 mRNA and protein expression were significantly increased. In KCs exposed to H/R as well as in liver tissues from HS mice, cytokine mRNA and protein levels (IL-1β, TNF-α, IL-6) were increased; however, ENOblock treatment significantly decreased these parameters. HS also markedly increased ENO1 activity and cleaved caspase-1 in KCs, while these parameters were significantly attenuated by ENOblock treatment. These findings suggest that targeting ENO1 in KCs could be a promising therapeutic strategy for mitigating HS-induced liver injury.