Pharmacological preconditioning with cilostazol reverses steatosis and protects the liver against ischemia-reperfusion injury in steatotic rats

Abstract Metabolic dysfunction-associated steatotic liver disease markedly increases susceptibility to hepatic ischemia–reperfusion injury during liver surgery. We investigated whether short-term pretreatment with the phosphodiesterase-3 inhibitor cilostazol protects steatotic livers in a fructose-induced rat model. Steatosis was induced by a 6-week high-fructose diet in Sprague–Dawley rats. Animals received cilostazol (5 mg/kg/day) or vehicle by oral gavage for 3 or 7 days before 60 min selective lobar ischemia followed by 2–24 h reperfusion. Hepatic arterial flow and microvascular perfusion were assessed by ultrasonic flowmetry and laser Doppler fluxmetry; serum transaminases were measured spectrophotometrically. Histology and immunohistochemistry were used to quantify steatosis, MPO-positive neutrophil infiltration, apoptosis, and hepatocellular cell-cycle-associated activity. Cilostazol pretreatment reduced steatosis, improved hepatic arterial and microvascular perfusion, limited hepatocellular apoptosis, and increased hepatocellular cell-cycle-associated activity compared with controls. Neutrophil infiltration was higher in cilostazol-treated animals than in controls after 2 h of reperfusion. However, it subsequently declined, whereas it continued to increase in controls, resulting in lower neutrophil counts in cilostazol-treated animals after 24 h of reperfusion. Overall, cilostazol pretreatment attenuated warm ischemia–reperfusion injury in steatotic livers by reducing steatosis, improving perfusion, limiting apoptosis, and increasing cell-cycle-associated activity, supporting further evaluation before hepatic surgery in steatotic livers.