Sildenafil for Attenuating Hepatic Ischemia-Reperfusion Injury and Promoting Liver Regeneration After Major (65%) Hepatectomy: A Porcine Pilot Study.

Introduction Hepatic ischemia-reperfusion (I/R) injury is a major driver of post-hepatectomy liver failure (PHLF) and contributes to morbidity after major liver resection. Sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor, has shown protective effects against I/R injury in cardiac, renal, and rodent hepatic models, but pre-clinical data in large animals undergoing major hepatectomy are scarce. The aim of this study is to evaluate whether perioperative oral sildenafil attenuates I/R injury and enhances liver regeneration after 65% hepatectomy combined with 45 minutes of warm ischemia in a porcine model. Methods Fourteen male domestic pigs (28-39 kg) were randomly allocated to two groups of seven. Animals in the control group (Group A) underwent 65% hepatectomy with 45 minutes of continuous portal triad clamping (Pringle maneuver). Animals in the sildenafil group (Group B) underwent the same operation but additionally received oral sildenafil 0.3 mg/kg every eight hours, beginning 24 hours before surgery and continuing for seven postoperative days. Hemodynamic parameters, arterial blood gases, liver function tests (including bilirubin and markers of hepatocellular injury (ALT, AST, LDH), prothrombin time (PT), aPTT), and inflammatory markers (tumor necrosis factor-α (TNF-α), IL-1, IL-6, malondialdehyde (MDA), C-reactive protein) were measured at predefined time points up to 24 hours from reperfusion and on postoperative day 7. Histopathology and immunohistochemistry (PCNA, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling), myeloperoxidase (MPO), Ki-67) were performed on baseline and day 7 wedge liver biopsies. Macroscopic liver regeneration was quantified by liver weight and volume measurements at sacrifice on postoperative day 7. The Mann-Whitney U test was used for continuous variables, with p < 0.05 considered statistically significant. Results Body weight, hepatectomy percentage, and intraoperative hemodynamics were comparable between the two groups. Mean arterial lactate at the end of ischemia (5.98 vs. 2.85 mmol/L, p = 0.005) and at 24 hours of reperfusion (2.10 vs. 1.11 mmol/L, p < 0.001) was significantly lower in the sildenafil group. ALT, AST, and LDH were significantly lower in the sildenafil group at 24 hours after reperfusion and at postoperative day 7 (all p ≤ 0.05). At six hours of reperfusion, TNF-α (4.84 vs. 11.17 pg/mL, p = 0.018) and IL-1 (3.09 vs. 7.47 pg/mL, p = 0.013) were lower in the sildenafil group, while IL-6 was higher (5.86 vs. 3.90 pg/mL, p = 0.017), consistent with a hepatoprotective IL-6 response. Histology also demonstrated decreased hepatocellular necrosis and a higher overall histopathological score in the control group (116 vs. 58, p = 0.025). Macroscopic regeneration of the remnant liver volume by postoperative day 7 was 22.5% in the sildenafil group versus 13.9% in controls (p = 0.002). One control animal in the control group died on postoperative day 3 from acute liver failure (mortality 14.3% vs. 0%). Conclusions In this porcine pilot study, perioperative oral sildenafil attenuated hepatocellular injury and the early systemic inflammatory response, and improved macroscopic liver regeneration after major hepatectomy with warm ischemia. These findings extend prior rodent observations into a clinically relevant large-animal model and support further translational evaluation of PDE-5 inhibition as a hepatoprotective strategy in major liver surgery and transplantation.