Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK.

PURPOSE: Curcumin, a biphenolic compound extracted from turmeric (Curcuma longa), possesses potent anti-inflammatory activity. The present study investigated whether curcumin could increase 5' adenosine monophosphate-activated protein kinase (AMPK) activity in macrophages and modulate the severity of lipopolysaccharide (LPS)-induced acute lung injury. METHODS: Macrophages were treated with curcumin and then exposed (or not) to LPS. Acute lung injury was induced by intratracheal administration of LPS in BALB/c mice. RESULTS: Curcumin increased phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in a time- and concentration-dependent manner. Curcumin did not increase phosphorylation of liver kinase B1, a primary kinase upstream of AMPK. STO-609, an inhibitor of calcium(2+)/calmodulin-dependent protein kinase kinase, diminished curcumin-induced AMPK phosphorylation, but transforming growth factor-beta-activated kinase 1 inhibitor did not. Curcumin also diminished the LPS-induced increase in phosphorylation of inhibitory κB-alpha and the production of tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein (MIP)-2, and interleukin (IL)-6 by macrophages. Systemic administration of curcumin significantly decreased the production of TNF-α, MIP-2, and IL-6 as well as neutrophil accumulation in bronchoalveolar lavage fluid, and also decreased pulmonary myeloperoxidase levels and the wet/dry weight ratio in mice subjected to LPS treatment. CONCLUSION: These results suggest that the protective effect of curcumin on LPS-induced acute lung injury is associated with AMPK activation.

Current status of intensive care units registered as critical care subspecialty training hospitals in Korea.

There is a lack of information on critical care in Korea. The aim of this study was to determine the current status of Korean intensive care units (ICUs), focusing on the organization, characteristics of admitted patients, and nurse and physician staffing. Critical care specialists in charge of all 105 critical care specialty training hospitals nationwide completed a questionnaire survey. Among the ICUs, 56.4% were located in or near the capital city. Only 38 ICUs (17.3%) had intensive care specialists with a 5-day work week. The average daytime nurse-to-patient ratio was 1:2.7. Elderly people ≥ 65 yr of age comprised 53% of the adult patients. The most common reasons for admission to adult ICUs were respiratory insufficiency and postoperative management. Nurse and physician staffing was insufficient for the appropriate critical care in many ICUs. Staffing was worse in areas outside the capital city. Much effort, including enhanced reimbursement of critical care costs, must be made to improve the quality of critical care at the national level.

Propofol attenuates pulmonary injury induced by collapse and reventilation of lung in rabbits.

Propofol is an anesthetic drug with antioxidant and anti-inflammatory properties. We previously found that propofol attenuated lipopolysaccharide-induced acute lung injury in rabbits. This study was performed to evaluate the effects of propofol on lung injury caused by collapse and reventilation in rabbits. The wet/dry weight ratio of the lung, lung injury scores, percentage of polymorphonuclear leukocytes, albumin concentration, malondialdehyde, and interleukin-8 levels in bronchoalveolar lavage fluid were significantly increased in both lungs of the reventilation group. The degree of increase in these parameters was more significant in the right (reventilated) than in the left (non-reventilated) lung. Propofol attenuated these changes. These findings suggest that reventilation of a collapsed lung can cause injury in the contralateral non-reventilated lung as well as the reventilated lung. Propofol may provide a beneficial effect on lung injury induced by collapse and reventilation of the lung.

Anesthetic requirements and stress hormone responses in chronic spinal cord-injured patients undergoing surgery below the level of injury: nitrous oxide vs remifentanil.

BACKGROUND: Nitrous oxide (N2O) and remifentanil both have anesthetic-reducing and antinociceptive effects. We aimed to determine the anesthetic requirements and stress hormone responses in spinal cord-injured (SCI) patients undergoing surgery under sevoflurane anesthesia with or without pharmacodynamically equivalent doses of N2O or remifentanil. METHODS: Forty-five chronic, complete SCI patients undergoing surgery below the level of injury were randomly allocated to receive sevoflurane alone (control, n = 15), or in combination with 67% N2O (n = 15) or target-controlled infusion of 1.37 ng/ml remifentanil (n = 15). Sevoflurane concentrations were titrated to maintain a Bispectral Index (BIS) value between 40 and 50. Measurements included end-tidal sevoflurane concentrations, mean arterial blood pressure (MAP), heart rate (HR), and plasma catecholamine and cortisol concentrations. RESULTS: During surgery, MAP, HR, and BIS did not differ among the groups. Sevoflurane concentrations were lower in the N2O group (0.94 ± 0.30%) and the remifentanil group (1.06 ± 0.29%) than in the control group (1.55 ± 0.34%) (P < 0.001, both). Plasma concentrations of norepinephrine remained unchanged compared to baseline values in each group, with no significant differences among groups throughout the study. Cortisol levels decreased during surgery as compared to baseline values, and returned to levels higher than baseline at 1 h after surgery (P < 0.05) without inter-group differences. CONCLUSIONS: Remifentanil (1.37 ng/ml) and N2O (67%) reduced the sevoflurane requirements similarly by 31-39%, with no significant differences in hemodynamic and neuroendocrine responses. Either remifentanil or N2O can be used as an anesthetic adjuvant during sevoflurane anesthesia in SCI patients undergoing surgery below the level of injury.

Urinary trypsin inhibitor attenuates liver enzyme elevation after liver resection.

BACKGROUND: Urinary trypsin inhibitors (UTI) have been widely used for the treatment of diseases including disseminated intravascular coagulation, shock, and pancreatitis. Since UTI synthesis is likely to be reduced in patients who have undergone liver resection, the incidence of inflammatory reactions may be increasing accordingly. For such patients, the liver enzyme increases after the operation can reflect liver damage. The purpose of this study was to examine if ulinastatin can inhibit liver enzyme increases after liver resection. METHODS: After receiving Institutional Review Board approval, a retrospective chart review was performed on 201 patients who underwent hepatic resection from 2006 to 2010. We divided the records into the control (n = 69) and ulinastatin (n = 132) groups according to the use of intraoperative ulinastatin and compared the preoperative and postoperative laboratory test results. The number of patients who had > 400 U/L elevation of aspartate transaminase (AST) level after surgery was compared between the 2 groups. RESULTS: The mean AST, alanine transaminase (ALT), and total bilirubin levels after liver resection were significantly lower in the ulinastatin group than in the control group. The number of patients who showed an AST > 400 U/L after liver resection was significantly higher in the control group (odds ratio = 3.02). CONCLUSIONS: Ulinastatin attenuates the elevation of hepatic enzymes and bilirubin after liver resection.

Curcumin protects against regional myocardial ischemia/reperfusion injury through activation of RISK/GSK-3ß and inhibition of p38 MAPK and JNK.

BACKGROUND: Curcumin, the active ingredient of turmeric (Curcuma longa), is known to have anti-inflammatory and antioxidative properties. The present study was aimed to determine the effect of curcumin in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases and apoptotic kinases. METHODS: Sprague-Dawley rats (n = 109) subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion followed by reperfusion were assigned to receive saline (control), curcumin (100 mg/kg), wortmannin (inhibitor of phosphatidylinositol-3-OH kinase [PI3K]-Akt), wortmannin + curcumin, U0126 (inhibitor of extracellular signal-regulated kinase [ERK1/2]), U0126 + curcumin, SB216763 (inhibitor of glycogen synthase kinase [GSK-3ß]), and SB216763 + curcumin 20 minutes before LAD occlusion. Infarct size was measured after 2 hours of reperfusion by triphenyl tetrazolium chloride staining. The phosphorylation of Akt, ERK1/2, GSK-3ß, p38, and c-Jun N-terminal kinases (JNK) was determined by immunoblotting after 10 minutes of reperfusion. RESULTS: Curcumin significantly reduced the infarct size compared with the control (33.1% ± 6.2% vs 50.1% ± 3.9%; P < .05). Wortmannin or U0126 alone did not affect the infarct size but abolished the curcumin-induced cardioprotective effect. Curcumin significantly enhanced the phosphorylation of Akt, ERK1/2, and GSK-3ß, while it reduced that of p38 and JNK. Wortmannin or U0126 abolished enhanced phosphorylation of GSK-3ß induced by curcumin. SB216763 alone or combined with curcumin reduced the infarct size and enhanced phosphorylation of GSK-3ß compared with the control. CONCLUSIONS: Preconditioning by curcumin effectively protects against regional myocardial I/R injury through the activation of prosurvival kinases involving PI3K-Akt, ERK1/2, and GSK-3ß, and attenuation of p38 and JNK.

Effect of manassantin B, a lignan isolated from Saururus chinensis, on lipopolysaccharide-induced interleukin-1ß in RAW 264.7 cells.

BACKGROUND: Elevated systemic levels of pro-inflammatory cytokines cause hypotension during septic shock and induce capillary leakage in acute lung injury. Manassantin B has anti-inflammatory and anti-plasmoidal properties. This study examined the effects of manassantin B on lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages. METHODS: RAW 264.7 macrophage cells were incubated without or with (1, 3 and 10 µM) manassantin B and without or with (100 ng/ml) LPS. Manassantin B dissolved in phosphate buffered saline was added to the medium 1 h prior to the addition of LPS. The degree of activation of mitogen-activated protein kinase (MAPK) including extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino terminal kinases (JNK) and p38 MAPK, and the level of interleukin (IL)-1ß were determined 30 min and 24 h after the addition of LPS respectively. RESULTS: Manassantin B inhibited the production of IL-1ß and attenuated the phosphorylations of ERK1/2 and p38 MAPK, but not that of JNK, in RAW 264.7 cells treated with LPS. CONCLUSIONS: Manassantin B reduces LPS-induced IL-1ß expression through effects on ERK1/2- and p38 MAPK-mediated pathways. Manassantin B has potential as a potent anti-inflammatory drug for use in pathological processes such as sepsis or acute lung injury.

Effects of urinary trypsin inhibitor on lipopolysaccharide-induced acute lung injury in rabbits.

This study was undertaken to clarify the effects of urinary trypsin inhibitor (UTI) on lipopolysaccharide (LPS)-induced acute lung injury. Rabbits were randomly assigned to one of seven groups: saline only, UTI, LPS, pre- or post-UTI-high (infusion of UTI of 25,000 U/kg followed by 25,000 U/kg over 2 h), pre- or post-UTI-low (infusion of UTI of 2,500 U/kg followed by 2,500 U/kg over 2 h). UTI was administered 30 min before (pre-groups) or 15 min after (post-groups) LPS administration. Rabbits were mechanically ventilated with 40% oxygen for 6 h. LPS decreased peripheral blood leukocyte counts and increased wet/dry weight ratio of lung, lung injury score, neutrophil infiltration in lung, and IL-8 production in systemic blood and bronchoalveolar lavage fluid (BALF). Rabbits treated by UTI were protected from LPS-induced lung injury, as determined by wet/dry weight ratio, neutrophil infiltration in lung, lung injury score, and IL-8 in BALF levels. UTI attenuated LPS-induced acute lung injury in rabbits mainly by inhibiting neutrophil and IL-8 responses, which may play a central role in sepsis-related lung injury.

Neuroprotective effects of remifentanil against transient focal cerebral ischemia in rats.

BACKGROUND: Opioid agonists have been implicated in neuroprotection from hypoxic injury through regulating mitogen-activated protein kinases and cytokines. We determined the effects of remifentanil in focal brain ischemia and reperfusion (I/R) injury. Mechanisms linked to mitogen-activated protein kinases, including extracellular signaling-regulated kinase (ERK) 1/2, p38 kinases, and c-Jun N-terminal kinase (JNK), and various cytokines were also examined. METHODS: Male Sprague-Dawley rats were subjected to an I/R insult consisting of 90 minutes' middle cerebral artery occlusion (MCAO) followed by reperfusion under general anesthesia. Neurological deficit scores and infarct volume were determined after 24 hours of reperfusion. Remifentanil (5 µg/kg/min) was given alone or combined with naltrindole (δ-opioid receptor antagonist; 1 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (µ-opioid receptor antagonist; 1 mg/kg), or 5'-guanidinonaltrindole (κ-opioid receptor antagonist; 1 mg/kg). Opioid antagonists were administered 20 minutes before MCAO. Remifentanil infusion was started 10 minutes before MCAO and continued throughout. The control group was without drugs. The expression levels of ERK1/2, p38, and JNK, and also those of tumor necrosis factor-α (TNF-α) and interleukin-6, were determined after 1, 3, and 24 hours of reperfusion. RESULTS: Remifentanil significantly improved the functional outcome and reduced the infarct volumes (69.0±24.3 mm(3) vs. 108.9±24.8 mm(3)), which were not affected by D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) or 5'-guanidinonaltrindole, but were abolished by naltrindole. The I/R insult enhanced the phosphorylation of ERK 1/2 and the expression of TNF-α, which were significantly reduced by remifentanil. Neither the phosphorylation of p38 and JNK nor the production of interleukin-6 was altered throughout the experiment. CONCLUSIONS: Remifentanil may be neuroprotective against focal I/R injury, possibly through the activation of δ-opioid receptors and attenuation of ERK 1/2 activity and TNF-α production, in the rat brain.

Inverted takotsubo-like left ventricular dysfunction with pulmonary oedema developed after caesarean delivery complicated by massive haemorrhage in a severe preeclamptic parturient with a prolonged painful labour.

Inverted takotsubo cardiomyopathy (TTC), a variant of stress-induced cardiomyopathy, features transient myocardial dysfunction characterized by a hyperdynamic left ventricular apex and akinesia of the base. Herein, we describe a 38-year-old primigravida with severe preeclampsia who had active labour for 4 h followed by an emergency caesarean delivery. She developed postpartum haemorrhage due to uterine atony complicated by pulmonary oedema, which was managed with large-volume infusion and hysterectomy. Her haemodynamic instability was associated with cardiac biomarkers indicative of diffuse myocardial injury and echocardiographic findings of an "inverted" TTC. The patient was almost fully recovered one month later. Our case shows that a reversible inverted TTC may result from a prolonged painful labour. TTC should be listed in the differential diagnosis of the patient presenting with pulmonary oedema of unknown origin, especially in patients with severe preeclampsia.

Sauchinone, a lignan from Saururus chinensis, reduces tumor necrosis factor-alpha production through the inhibition of c-raf/MEK1/2/ERK 1/2 pathway activation.

We investigated the anti-inflammatory effects of sauchinone, a lignan isolated from Saururus chinensis, and the underlying mechanism in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. To assess the effects of sauchinone on LPS-induced macrophages activation, we measured the production of tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2, and activation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) 1/2, c-Jun amino terminal kinases and p38 mitogen-activated protein kinase, and NF-kappaB activation in RAW264.7 cells. Sauchinone decreased the production of TNF-alpha, but not MIP-2 production in RAW264.7 cells stimulated with LPS. Sauchinone also decreased c-Raf-MEK1/2-ERK1/2 phosphorylation and NF-kappaB activation in RAW264.7 cells stimulated with LPS. Our results show that sauchinone inhibits LPS-induced TNF-alpha expression in macrophages by suppression of NF-kappaB activation via ERK1/2 pathway, which may constitute anti-inflammatory effects of sauchinone.

The effect of epigallocatechin gallate on lipopolysaccharide-induced acute lung injury in a murine model.

This study was performed to evaluate the effects of epigallocatechin 3 gallate (EGCG) on lipopolysaccharide (LPS)-induced acute lung injury in a murine model. In the present study, production of TNF-alpha and MIP-2 and activation of extracellular signal-regulated kinases (ERK)1/2, c-Jun amino terminal kinases (JNK) and p38 in RAW264.7 cells were measured. EGCG inhibited the production of TNF-alpha and MIP-2, and attenuated phosphorylation levels of ERK1/2 and JNK, but not p38 in RAW264.7 cells stimulated with LPS. Also, EGCG attenuated the production of TNF-alpha and MIP-2, and the phosphorylation of ERK1/2 and JNK in the lungs of mice administered with LPS intratracheally. It reduced wet/dry weight ratio, histological severities, and neutrophil accumulation in the lungs in mice given LPS. Our results showed that EGCG attenuated LPS-induced lung injury by suppression of the MIP-2 and TNF-alpha production, and ERK1/2 and JNK activation in macrophage stimulated with LPS.