Sang Hyun Kwak

Epigallocatechin-3-gallate, a green tea catechin, protects the heart against regional ischemia–reperfusion injuries through activation of RISK survival pathways in rats

Epigallocatechin-3-gallate (EGCG), the major catechin derived from green tea, has been shown to modulate numerous molecular targets in the setting of inflammation. This study aimed to determine whether EGCG protects against regional myocardial ischemia/reperfusion (I/R) injuries and its underlying mechanisms involving the role of reperfusion injury salvage kinase (RISK) pathways (PI3K-Akt and ERK 1/2) and GSK-3β or apoptotic kinases (p38 and JNK). The rats were subjected to I/R injuries consisting of 30xa0min ischemia followed by 2xa0h reperfusion. EGCG (10xa0mg/kg, intravenously) was administered alone or along with wortmannin (PI3K inhibitor, 0.6xa0mg/kg, intravenously) 5xa0min before the onset of reperfusion. Wortmannin was administered 10xa0min before the reperfusion. Infarct size was measured at the end of the reperfusion. The phosphorylation of Akt, GSK-3β, and MAPK kinases (ERK1/2, P38 and JNK) was determined by Western blotting after 10xa0min of reperfusion. EGCG reduced the infarct size compared with the control (25.4xa0±xa09.2 versus 43.2xa0±xa08.2xa0%, pxa0<xa00.05). Wortmannin alone did not affect the infarct size, but abolished the EGCG-induced infarct size limiting effect, indicating that EGCG may protect the heart by modulating the PI3K-Akt. EGCG significantly enhanced the phosphorylation of Akt and GSK-3β but not ERK1/2, while it reduced that of p38 and JNK. These results suggest that EGCG has a protective effect against regional myocardial I/R injuries through activation of the RISK pathway and attenuation of p38 and JNK. EGCG may have cardioprotective effects in patients undergoing surgeries prone to myocardial I/R injuries.

Clinical Practice Guideline of Acute Respiratory Distress Syndrome

There is no well-stated practical guideline for mechanically ventilated patients with or without acute respiratory distress syndrome (ARDS). We generate strong (1) and weak (2) grade of recommendations based on high (A), moderate (B) and low (C) grade in the quality of evidence. In patients with ARDS, we recommend low tidal volume ventilation (1A) and prone position if it is not contraindicated (1B) to reduce their mortality. However, we did not support high-frequency oscillatory ventilation (1B) and inhaled nitric oxide (1A) as a standard treatment. We also suggest high positive end-expiratory pressure (2B), extracorporeal membrane oxygenation as a rescue therapy (2C), and neuromuscular blockage for 48 hours after starting mechanical ventilation (2B). The application of recruitment maneuver may reduce mortality (2B), however, the use of systemic steroids cannot reduce mortality (2B). In mechanically ventilated patients, we recommend light sedation (1B) and low tidal volume even without ARDS (1B) and suggest lung protective ventilation strategy during the operation to lower the incidence of lung complications including ARDS (2B). Early tracheostomy in mechanically ventilated patients can be performed only in limited patients (2A). In conclusion, of 12 recommendations, nine were in the management of ARDS, and three for mechanically ventilated patients.

Protective Effect of Sauchinone Against Regional Myocardial Ischemia/Reperfusion Injury: Inhibition of p38 MAPK and JNK Death Signaling Pathways

Sauchinone has been known to have anti-inflammatory and antioxidant effects. We determined whether sauchinone is beneficial in regional myocardial ischemia/reperfusion (I/R) injury. Rats were subjected to 20 min occlusion of the left anterior descending coronary artery, followed by 2 hr reperfusion. Sauchinone (10 mg/kg) was administered intraperitoneally 30 min before the onset of ischemia. The infarct size was measured 2 hr after resuming the perfusion. The expression of cell death kinases (p38 and JNK) and reperfusion injury salvage kinases (phosphatidylinositol-3-OH kinases-Akt, extra-cellular signal-regulated kinases [ERK1/2])/glycogen synthase kinase (GSK)-3β was determined 5 min after resuming the perfusion. Sauchinone significantly reduced the infarct size (29.0% ± 5.3% in the sauchinone group vs 44.4% ± 6.1% in the control, P < 0.05). Accordingly, the phosphorylation of JNK and p38 was significantly attenuated, while that of ERK1/2, Akt and GSK-3β was not affected. It is suggested that sauchinone protects against regional myocardial I/R injury through inhibition of phosphorylation of p38 and JNK death signaling pathways.

Effects on Intubating Conditions of Pretreatment with Remifentanil before Administration of Cisatracurium

Cisatracurium provides superior hemodynamic stability with only minor release of histamine, and its metabolism via Hoffman elimination is independent of organ function. However, use of cisatracurium is limited because of reportedly slower onset and unsatisfactory intubating conditions. Many studies have shown that remifentanil might provide reliable intubating conditions; thus, we hypothesized that pretreatment with remifentanil before administration of cisatracurium might result in acceptable intubating conditions. Sixty healthy patients scheduled for elective surgery were enrolled and randomly divided into three groups: saline (Group I, n=20), remifentanil 0.5 µg/kg (Group II, n=20), and remifentanil 1.0 µg/kg (Group III, n=20). The anesthesia was induced with propofol 2.0 µg/kg given intravenously over 30 s followed by injection over 30 s of a different dose of remifentanil according to the study protocol. We examined the intubating condition by jaw relaxation, vocal cord state, and diaphragmatic response 90 s after administering cisatracurium. We also measured mean blood pressure, heart rate, and the onset time, which is the interval from the end of neuromuscular blocking agent administration until suppression of maximal T1 on a train-of four sequence. The mean values of the intubating condition after endotracheal intubation in Groups II and III were significantly lower than that in Group I (p<0.005), although the overall onset time of cisatracurium did not differ significantly between the three groups. Our results suggest that supplementation with remifentanil in an induction regimen with cisatracurium improves the quality of the intubating condition even though the onset time of cisatracurium is not shortened.

The Effects of Flecainide Acetate on Inflammatory-Immune Response in Lipopolysaccharide-Stimulated Neutrophils and on Mortality in Septic Rats

Background Flecainide acetate is a drug used primarily for cardiac arrhythmia. Some studies also imply that flecainide acetate has the potential to regulate inflammatory-immune responses; however, its mechanism of action is contended. We determined the effects of flecainide acetate on lipopolysaccharide (LPS)-stimulated human neutrophils in vitro and on mortality in a septic rat model. Methods Neutrophils from human blood were cultured with varying concentrations of flecainide acetate (1 μM, 10 μM, or 100 μM) with or without LPS (100 ng/ml). To assess neutrophil activation, the protein levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and IL-8 were measured after a 4-hour culture period. To assess the intracellular signaling pathways, the levels of phosphorylation of p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) were measured after a 30-minute culture period, and the nuclear translocation of nuclear factor (NF)-κB was measured after a 1-hour culture period. Additionally, the survival rate was investigated in a rat sepsis model. Results Flecainide acetate down-regulated the activation of proinflammatory cytokines, including TNF-α and IL-6 and IL-8, and intracellular signaling pathways including ERK 1/2 and NF-κB. Flecainide acetate also improved the survival rate in the rat sepsis model. Conclusions Collectively, these findings indicate that flecainide acetate can improve survival in a rat sepsis model by attenuating LPS-induced neutrophil responses. We therefore suggest that flecainide acetate plays an important role in modulating inflammatory-immune responses.

Remifentanil Attenuates Systemic Inflammatory Response in Patientsundergoing Cardiac Surgery with Cardiopulmonary Bypass

Background: Systemic inflammatory response plays pivotal n roles in the pathogenesis of organ dysfunction after cardiac n surgery with cardiopulmonary bypass (CPB). The aim of this n study was to investigate whether remifentanil has the n effects on the systemic inflammatory response induced by n cardiac surgery with CPB. nMethods: Sixty adult patients undergoing cardiac surgery n with CPB were randomly assigned to two groups: a n remifentanil (n=30) and a fentanyl group (n=30). The plasma n levels of IL-6, IL-8 and malondialdehyde (MDA) were n measured at preinduction (T1), just before aortic clamping n (T2), just before aortic declamping (T3), 5 (T4), 30 (T5), and n 60 (T6) min after aortic declamping. Hemodynamic variables n serially recorded at that same times. Myocardial cell n damage as assessed by plasma level of creatine kinase-MB n (CK-MB) and troponin T were measured before and 24 n hours after surgery. nResults: The levels of IL-6, IL-8 and MDA significantly n increased from just before aortic declamping in both n groups. In the remifentanil group, all of those were n significantly lower compared to the fentanyl group from just n before aortic declamping (P<0.05). The level of CK-MB and n troponin T significantly increased at 24 hours after surgery n than preoperative baseline in both groups. In the n remifentanil group, both were significantly lower than n fentanyl group at 24 hours after surgery. nConclusion: Remifentanil attenuates systemic inflammatory n response more effectively than fentanyl in cardiac surgery n with CPB. The mechanism of its effects is likely to be n through proinflammatory cytokines (including IL-6, IL-8) and n oxidative stress mediator (MDA).