Propofol reduces hypoxia­induced autophagic cell death through downregulating HIF 1α in alveolar epithelial type II cells of rats.

Propofol (2,6­diisopropylphenol) exerts protective effects on alveolar epithelial type II (ATII) cells, partly through attenuating hypoxia­induced apoptosis. Autophagy is involved in the activation of apoptosis. Therefore, the present study investigated the modulating effect of propofol against autophagy in ATII cells under hypoxia. Western blot analysis was performed to detect the protein expression of the autophagy molecular marker, microtubule­associated protein 1 light chain 3 (LC3)­II, under various conditions. The effects of propofol on the accumulation of other autophagy­associated proteins and apoptosis­associated proteins were also determined using western blot analysis. The interactions between proteins were determined by co­immunoprecipitation. Apoptosis of the ATII cells was monitored using FITC­conjugated AV/PI staining. Furthermore, hypoxia­inducible factor 1α (HIF 1α) small interfering (si) RNA was designed to construct si­HIF 1α ATII cells. The efficiency of interference was measured using reverse transcription­quantitative polymerase chain reaction and western blot analyses. Following pre­treatment with propofol, the hypoxia­induced accumulation of LC3­II, HIF 1α and B­cell lymphoma­2 interacting protein 3 (Bnip3) were markedly decreased, accompanied with the activation of mammalian target of rapamycin. In addition, cleaved­poly ADP­ribose polymerase was suppressed, and hypoxia­induced autophagic cell death was inhibited by propofol pre­treatment. HIF 1α was inhibited by si­HIF 1α, which simultaneously suppressed Bnip3 and LC3­II under hypoxia. Taken together, propofol reduced hypoxia­induced autophagic cell death through reducing the expression of HIF 1α in ATII cells, indicating a novel strategy for modulating autophagy via propofol in hypoxic ATII cells.

Chitosan aerosol inhalation alleviates lipopolysaccharide- induced pulmonary fibrosis in rats.

PURPOSE: Pulmonary fibrosis (PF) is an insidiously progressive scarring disorder of the alveoli and is associated with high mortality. Currently, therapies available are associated with restricted efficacy and side effects. This study aimed to investigate the effect of chitosan aerosol inhalation on lipopolysaccharide (LPS)-induced pulmonary remodeling and fibrosis in rats. METHODS: A rat model of PF was established by intratracheal injection of LPS (5 mg/kg). Chitosan was nebulized to rats from day 4 to 28 after LPS injection. We analyzed the effect of chitosan on LPS-induced pulmonary remodeling and fibrosis by hematoxylin-eosin staining (HE), Masson staining, and the determination of the hydroxyproline content. The expression intensities of matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed by western blots. RESULTS: Histological assessments showed that chitosan aerosol inhalation attenuated the fibrotic changes in LPS-induced PF in rats. Compared with the LPS group, the fibrosis parameters were significantly improved in the LPS + chitosan group (LCh group), although not as good as those of the control group. The expressions of MMP-3 and TIMP-1 in the LCh group were markedly less than that of the LPS group on the 28th day. CONCLUSIONS: Our findings show that chitosan aerosol inhalation inhibits the expression of MMP-3 and TIMP-1, and ameliorates LPS-induced pulmonary remodeling and fibrosis in rats.

Dexmedetomidine for the management of awake fibreoptic intubation.

BACKGROUND: Awake fibreoptic intubation (AFOI) frequently requires sedation, anxiolysis and relief of discomfort without impairing ventilation and depressing cardiovascular function. The goal is to allow the patient to be responsive and co-operative. Medications such as fentanyl, remifentanil, midazolam and propofol have been reported to assist AFOI; however,these agents are associated with cardiovascular or respiratory adverse effects. Dexmedetomidine has been proposed as an alternative to facilitate AFOI. OBJECTIVES: The primary objective of this review is to evaluate and compare the efficacy and safety of dexmedetomidine in the management of patients with a difficult or unstable airway undergoing awake fibreoptic intubation (AFOI). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2012, Issue 5), MEDLINE (1966 to May 2012) through Ovid, EMBASE (1980 to May 2012) and Web of Science (1945 to May 2012); we screened the reference lists of all eligible trials and reviews to look for further trials and contacted authors of trials to ask for additional information. We searched for ongoing trials at http://www.controlledtrials.com/ and http://clinicaltrials.gov/ . We reran our search of all databases listed above on 21 November 2013. SELECTION CRITERIA: We included published and unpublished randomized controlled trials, regardless of blinding or language of publication, in participants 18 years of age or older who were scheduled for an elective AFOI because of an anticipated difficult airway. Participants received dexmedetomidine or control medications. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data on study design, participants, interventions and outcomes. We assessed risk of bias using The Cochrane Collaboration's tool. We estimated risk ratios (RRs) or mean differences (MDs) with 95% confidence internals (CIs) for outcomes with sufficient data; for other outcomes, we performed a qualitative analysis. MAIN RESULTS: We identified four randomized controlled trials (RCTs), which included 211 participants. The four trials compared dexmedetomidine with midazolam, fentanyl, propofol or a sodium chloride placebo, respectively. The trials showed low or unclear risk of bias primarily because information provided on allocation concealment and other potential sources of bias was inadequate. Owing to clinical heterogeneity and potential methodological heterogeneity, it was impossible to conduct a full meta-analysis. We described findings from individual studies or presented them in tabular form. Limited evidence was available for assessment of the outcomes of interest for this review. Results of the limited included trials showed that dexmedetomidine significantly reduced participants' discomfort with no significant differences in airway obstruction, low oxygen levels or treatment-emergent cardiovascular adverse events noted during AFOI compared with control groups. When the search was rerun (from May 2012 to November 2013), it was noted that four studies are awaiting assessment. We will deal with these studies when we update the review. AUTHORS' CONCLUSIONS: Small, limited trials provide weak evidence to support dexmedetomidine as an option for patients with an anticipated difficult airway who undergo AFOI. The findings of this review should be further corroborated by additional controlled investigations.

Rescue of cAMP response element-binding protein signaling reversed spatial memory retention impairments induced by subanesthetic dose of propofol.

AIMS: The intravenous anesthetic propofol caused episodic memory impairments in human. We hypothesized propofol caused episodic-like spatial memory retention but not acquisition impairments in rats and rescuing cAMP response element-binding protein (CREB) signaling using selective type IV phosphodiesterase (PDEIV) inhibitor rolipram reversed these effects. METHODS: Male Sprague-Dawley rats were randomized into four groups: control; propofol (25 mg/kg, intraperitoneal); rolipram; and rolipram + propofol (pretreatment of rolipram 25 min before propofol, 0.3 mg/kg, intraperitoneal). Sedation and motor coordination were evaluated 5, 15, and 25 min after propofol injection. Invisible Morris water maze (MWM) acquisition and probe test (memory retention) were performed 5 min and 24 h after propofol injection. Visible MWM training was simultaneously performed to resist nonspatial effects. Hippocampal CREB signaling was detected 5 min, 50 min, and 24 h after propofol administration. RESULTS: Rolipram did not change propofol-induced anesthetic/sedative states or impair motor skills. No difference was found on the latency to the platform during the visible MWM. Propofol impaired spatial memory retention but not acquisition. Rolipram reversed propofol-induced spatial memory impairments and suppression on cAMP levels, CaMKIIα and CREB phosphorylation, brain-derived neurotropic factor (BDNF) and Arc protein expression. CONCLUSIONS: Propofol caused spatial memory retention impairments but not acquisition inability possibly by inhibiting CREB signaling.

Dexmedetomidine versus morphine or fentanyl in the management of children after tonsillectomy and adenoidectomy: a meta-analysis of randomized controlled trials.

OBJECTIVES: The primary objective of this review was to evaluate and compare the efficacy and safety of dexmedetomidine hydrochloride with the efficacy and safety of opioids for postoperative management of children after tonsillectomy and adenoidectomy. METHODS: We searched the Cochrane Central Register of Controlled Trials (Central) in the Cochrane Library (most recent issue), Medline (1966 to date) through Ovid, Embase (1980 to date), and Web of Science (1945 to date). The number of patients who required rescue analgesics (morphine or fentanyl) in the postanesthesia care unit, the number of patients with emergence agitation, the number of patients with postoperative nausea and vomiting, the time to eye-opening in response to verbal stimuli, and the time to extubation were analyzed. RESULTS: We included 5 trials, consisting of 482 patients in total. There were no significant differences in the number of patients who required rescue analgesics in the postanesthesia care unit, the number of patients with emergence agitation, the number of patients with postoperative nausea and vomiting, or the time to extubation between patients who received dexmedetomidine and those who received opioids. Compared with opioids, dexmedetomidine was associated with a significantly decreased time to eye-opening in response to verbal stimuli (mean difference, -2.11 minutes; 95% confidence interval, -3.32 to -0.91 minutes; p = 0.0006). CONCLUSIONS: Intraoperative use of dexmedetomidine was as effective as opioids in preventing postoperative pain and emergence agitation in children who had undergone tonsillectomy and adenoidectomy.

Autologous transplantation of peripheral blood-derived circulating endothelial progenitor cells attenuates endotoxin-induced acute lung injury in rabbits by direct endothelial repair and indirect immunomodulation.

BACKGROUND: Studies have demonstrated the role of circulating endothelial progenitor cells (EPCs) in maintaining normal endothelial function and in endothelial repairing. This study was aimed to observe the protective effects of autologous transplantation of circulating EPCs against endotoxin-induced acute lung injury in rabbits and to investigate the underlying mechanisms. METHODS: One-hundred-and-fifty rabbits were enrolled. After acute lung injury was induced by endotoxin, autologous circulating EPCs, endothelial cell, or normal saline were transfused intravenously, respectively. Pao(2)/FiO(2) ratios, concentrations of plasma nitric oxide, malonyldialdehyde, and activity of superoxide dismutase were examined. The lung wet-to-dry weight ratios were counted; polymorphonuclear cell ratios and areas of hyaline membrane formation and hemorrhage were measured. The levels of interleukin-1ß, E-selectin, intercellular adhesion molecule-1, interleukin-10, vascular endothelial growth factor protein, and inducible nitric oxide synthase protein were analyzed. RESULTS: Pao(2)/FiO(2) ratios were significantly increased with EPC transfusion. Infiltration of polymorphonuclear cells, lung wet-to-dry weight ratios, and area of hyaline membrane and hemorrhage in lung tissue were significantly decreased after EPC transplantation. Plasma level of nitric oxide and malondialdehyde were significantly inhibited, and the activity of superoxide dismutase was enhanced in the EPC-treated animals. EPC transplantation significantly increased level of interleukin-10 and vascular endothelial growth factor protein and reduced levels of interleukin-1ß, E-selectin, intercellular adhesion molecule-1, and inducible nitric oxide synthase in injury lung tissues. CONCLUSIONS: Autologous transplantation of circulating EPCs can partly restore the pulmonary endothelial function and effectively attenuate endotoxin-induced acute lung injury by direct endothelial repair and indirect immunomodulation of antioxidation and antiinflammation.

Hydroxyethyl starch for cardiovascular surgery: a systematic review of randomized controlled trials.

PURPOSE: The objective of this study was to appraise the safety profiles of HES preparations and to find out which HES preparation was the most acceptable in cardiovascular surgery through a comparison with control solutions. METHODS: Pertinent randomized controlled trials were selected through a search of Pubmed, Embase, and Cochrane Controlled Trials Register. Quantitative and qualitative analysis was carried out to evaluate blood loss, blood transfusion, renal function, complications, reoperation, and mortality. RESULTS: A total of 3,234 patients from 52 randomized controlled trials were included. HES preparations versus control solutions in blood loss: HES 130 kD vs. albumin (SMD -0.61, 95% CI -0.82, -0.40), HES 200 kD vs. albumin (SMD -0.01, 95% CI -0.29, 0.28), HES 450 kD vs. albumin (SMD 0.47, 95% CI 0.26, 0.68). When comparing control solutions with HES preparations, 50% (HES 450 kD), 40.9% (HES 200 kD), and 18.2% (HES 130 kD) of the comparisons showed more blood/blood products infusion with HES than with control solutions. A numerically lower mortality rate seemed to be related to HES preparations (2.68 vs 4.23%). No difference was found in terms of complications, renal failure, or reoperation. CONCLUSIONS: Perioperative administration of HES preparations is comparatively safe. The data appraising safety profiles of HES preparations are insufficient to make direct comparisons among themselves. As the third generation of HES preparations, HES 130 kD showed a trend toward lower blood loss and transfusion rates and is a suitable choice for cardiovascular surgery.

[Changes in alpha2-adrenergic receptors gene expression after high-level spinal cord injury in Wistar rats].

OBJECTIVE: To evaluate the change in alpha(2)-adrenergic receptors (alpha(2)-ARs) gene expression after high-level injury of the spinal cord (SCI), aiming as developing a more effective perioperative anesthetic management for high-level SCI patients. METHODS: Adult male Wistar rats were anesthetized and severe spinal crush injury at T4 was produced using modified Allens device. The expression of alpha(2)-ARs mRNA at different levels of spinal cord in normal control rats (C), injured segment (I), above (A) and below (B) the site of injured segment, were measured by reverse transcription-polymerase chain reaction (RT-PCR) 1 day, 3 days, 1 week, 2 weeks, 3 weeks and 4 weeks, respectively after SCI. RESULTS: Compared with group C (sham group), in group A the expression of alpha(2)-ARs mRNA decreased 1 day after SCI (P<0.05) and dropped to the nadir 2 weeks later (P<0.01), but the expression was restored to the normal level 4 weeks later. In group I the lowering of alpha(2)-ARs mRNA expression occurred immediately after SCI and down to the lowest value 1 week later (P<0.01), and did not recover to normal level 4 weeks later (P<0.05). In group B downregulation of alpha(2)-ARs mRNA expression was detected 1 day after SCI (P<0.05), but it was upregulated 1 week later reaching the normal level, which was maintained for 4 weeks. CONCLUSION: In a chronic SCI rat model, alpha(2)-ARs gene expression is downregulated in the injured segment, but returns to the normal level above and below the injured segment. The changes in alpha(2)-ARs may be a pivotal factor contributing to a series of abnormal responses after high-level SCI.

[Effect of high level spinal cord injury on rat heart function].

OBJECTIVE: To study the effects of high level spinal cord injury (SCI) on rat heart, and investigate the role of endothelin-1 (ET-1) in the harmful effects on heart after SCI. METHODS: Forty-eight male SD rats were randomly divided into six groups of 8 animals each: control group; 4-hour group: 4 th hour after injury to spinal cord at cervical 7 level; 12-hour group: 12 th hour after injury to 7 spinal cord at C7 level; 24-hour group with same injury; 48-hour group and 72-hour group, all with same injury. Mean arterial pressure (MAP), heart rate (HR), left ventricle systolic pressure (LVSP), and left ventricular maximum velocities of contraction (+/-dp/dt max) were recorded in each group. Lactate dehydrogenase (LDH), creatine kinase (CK), MB isoenzyme of creatine kinase (CK-MB) and ET-1 contents in the myocardium. were also measured. Specimens of the myocardium were harvested for ultrastructure examination with transmission electron microscopy. RESULTS: Hemodynamics variables including HR, MAP, LVSP and+/-dp/dtmax were significantly decreased in all the injury groups compared with that of control group (P<0.05 or P<0.01). These variables in 12-hour group showed lowest values among all the groups (all P<0.01). But the values of cardiac enzymes were much higher in five injury groups compared with that of control group (P<0.05 or P<0.01). ET-1 contents in serum and cardiac tissue raised markedly after the injury was inflicted to the animals (P<0.05), reaching peak at 12 hours (P<0.01). Ultrastructural examination of the myocardial tissue demonstrated that there were mild dissolution of myocardial fibrils and vacuolation of mitochondria at 12 hours after injury. CONCLUSION: High level SCI could induce myocardial injuries and an excessive production of ET-1 in circulation and myocardial tissue might play a role in myocardial damage after injury of the spinal cord at a high level.