Integrated stress response activation after recovery of cardiopulmonary bypass in rats

Abstract

The systemic inflammation response syndrome (SIRS) is a consequence of the cardiopulmonary bypass (CPB) in cardiac surgery that can trigger multiple organ dysfunction (MOD). Pulmonary, renal and cerebral dysfunctions are the most common post-operative complications of CPB. The sustained of activation of integrated stress response (ISR) pathway could impact patient outcomes. This project aims to decipher pathophysiological process in SIRS and organ dysfunction after recovery of CPB in a rat model. After isoflurane induction (2%, O 2 : 0.5 L/min) surgical procedure for CPB or Sham was performed under propofol-fentanyl infusion (30–4 μg/kg/h) on mechanically ventilated 15-week old rats. The CPB circuit allows blood to be drawn by the vena cava and reperfused in the aorta after oxygenation. Hemodynamic and biochemical parameters were monitored during the procedure. Mean Arterial Pressure (MAP) was maintained to a minimum of 60 mmHg with a FiO 2 1.0 for 1 h. Five hours post-recovery, behavior, respiratory rate and hemodynamic were measured. Blood and organs were collected to evaluate the integrated stress response pathway. Compared to Sham, CPB leads to a decrease of MAP (88.3 ± 2.6 vs 60.0 ± 9.4 mmHg, P < 0.05, N = 4), an increase of Lactate (1.4 ± 0.4 vs 4.1 ± 0.9 mM, P < 0.05), Creatinine (34.7 ± 1.0 vs 152.7 ± 7.7 μM, P < 0.05), and pro-inflammatory cytokines IL-6 (Sham: 48 ± 24 pg/mL; CPB: 8468 ± 1 pg/mL, P < 0.05). Rat Behavior and reflex, and lung inflammation were significantly altered 5 h after recovery when compared to Sham. ISR pathway activation was shown by western blot on lung, kidney and brain tissues from CPB rats with respectively a 3-, 2- and 3-fold increase in GADD34 protein levels. On our CPB rat model, we highlight organs dysfunctions associated with an activation of the ISR pathway. We will now evaluate the potential impact of ISR activation on MOD.