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Anesth Analg 2008; 107:1884-1891
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e3181884bbf
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ANESTHETIC PHARMACOLOGY

Propofol Pretreatment Reduces Ceramide Production and Attenuates Intestinal Mucosal Apoptosis Induced by Intestinal Ischemia/Reperfusion in Rats

Ke-Xuan Liu, PhD, MD*, Shu-Qing Chen, PhD, MD{dagger}, Wen-Qi Huang, MD*, Yun-Sheng Li, MD*, Michael G. Irwin, MD{ddagger}, and Zhengyuan Xia, PhD, MD{ddagger}

From the Departments of *Anesthesiology, {dagger}Gynecology and Obstetrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; and {ddagger}Department of Anesthesiology, University of Hong Kong, Hong Kong SAR, China.

Address correspondence and reprint requests to Dr. Ke-Xuan Liu, Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhongshan 2th Rd., Guangzhou, China, 510080. Address e-mail to liukexuan807{at}yahoo.com.cn.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Apoptosis has been shown to be a major mode of intestinal epithelial cell death caused by intestinal ischemia/reperfusion (II/R), a condition that is associated with increased oxidative stress. Ceramide has been proposed as a messenger of apoptosis. We investigated if pretreatment with propofol, an anesthetic with antioxidant properties, could reduce ceramide production, and consequently, mucosal epithelial apoptosis induced by II/R in rats.

METHODS: Rat II/R injury was produced by clamping the superior mesenteric artery for 1 h followed by 3 h of reperfusion. Thirty rats were randomly allocated into control, injury (II/R) and propofol (pretreatment) groups (n = 10 per group). In the propofol group, propofol 50 mg/kg, a dose that has been shown to cause the loss of reflex responses to a painful stimulus while remaining sensitive to skin incision in rats, was administered intraperitoneally 30 min before inducing intestinal ischemia, while animals in control and untreated injury groups received an equal volume of intralipid. Intestinal mucosal epithelial apoptosis was detected via electron microscopy and TUNEL analysis. Lipid oxidation product malondialdehyde and the activities of superoxide dismutase were assessed by colorimetric analyses. Ceramide generation and sphingomyelinase mRNA expression in intestinal mucosa were determined by high performance thin layer chromatography and reverse transcriptase polymerase chain reaction, respectively.

RESULTS: II/R caused intestinal mucosal epithelial apoptosis and over-production of ceramide accompanied by up-regulation of sphingomyelinase mRNA expression and increases in lipid oxidation (all P < 0.01 versus control). Propofol pretreatment significantly attenuated these changes (all P < 0.01, propofol versus injury).

CONCLUSION: The findings indicate that propofol pretreatment attenuates II/R-induced intestinal epithelial apoptosis, which might be attributable to its antioxidant property modulating the ceramide pathway.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Intestinal ischemia/reperfusion (II/R) injury is a potentially serious consequence of acute mesenteric ischemia, hemorrhagic, traumatic or septic shock, severe burns or some surgical procedures, including small bowel transplantation and abdominal aortic surgery.1 II/R leads not only to injury of the intestine itself, but also involves severe destruction of distant tissue due to disruption of the intestinal mucosal barrier which causes a systemic inflammatory reaction. II/R can even result in multiple organ dysfunction.2,3

Intestinal mucosal epithelial cells are the main component of the intestinal mucosal barrier. Apoptosis is a major mode of cell death in the destruction of rat small intestinal epithelial cells induced by ischemia and I/R injury.4–6 Therefore, prophylactic antiapoptotic treatment could be an effective therapeutic strategy for the prevention of II/R injury, which has been demonstrated by various studies.7–9

Ceramide, a novel second messenger, plays an important role in a variety of physiologic and pathologic events, including apoptosis and injuries.10 Modulation of ceramide levels may be regarded as a novel therapeutic approach.11 The intracellular concentration of ceramide can be influenced by many inducers, including reactive oxygen species (ROS) and IR injury.12 Recently, we demonstrated that ceramide contributes to the intestinal mucosal cell apoptosis induced by II/R.9

Propofol, an IV anesthetic with antioxidant properties,13,14 is commonly used for the induction and maintenance of anesthesia during surgery and for postoperative sedation.15–17 We have recently demonstrated that pretreatment with propofol at a sedative dose attenuated intestinal mucosal injury induced by II/R in rats.18 It is unknown, however, whether its protection of intestinal mucosa is due to its effect against intestinal mucosal cell apoptosis.

Based on the above findings, we hypothesized that moderate pretreatment doses of propofol would decrease intestinal mucosal cell apoptosis. The present study was designed to investigate the effect of propofol pretreatment on II/R-induced intestinal mucosal epithelial apoptosis as well as its effects on ceramide signaling.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal Model
The current study was approved by the Animal Care Committee of Sun Yat-sen University, Guangzhou, China and was performed in accordance with National Institutes of Health guidelines for the use of experimental animals. Thirty adult pathogen-free male Wistar rats weighing between 240 and 305 g, were housed in individual cages in a temperature-controlled room with alternating 12 h light/dark cycles and acclimatized for 1 wk before the study. Food was removed 8 h before the study, but all animals had free access to water. All animals were anesthetized with pentobarbital (30 mg/kg body weight, intraperitoneally [ip]), and the small intestine was exteriorized by midline laparotomy. The II/R injury was established by occluding the superior mesenteric artery (SMA) with a microvessel clip for 1 h followed by 3 h reperfusion as previously described.9,18 Ischemia was recognized by the development of pulselessness and pale color of the small intestine. The return of pulses and the reestablishment of the pink color were assumed to indicate valid reperfusion.

Experimental Protocol
The rats were randomly allocated into 1 of the 3 groups (n = 10 per group): i) control group (control), in which sham surgical preparation including isolation of the SMA without occlusion was performed; ii) injury group (injury), in which II/R was produced by clamping the SMA (ischemia) for 1 h followed by declamping the SMA (reperfusion) for 3 h; iii) Propofol pretreatment group (propofol), in which propofol was given 30 min before intestinal ischemia was induced. In the treatment groups, propofol (Diprivan, propofol 1%, CG411, AstraZeneca, Caponago, Italy) 50 mg/kg was administrated ip. Animals in the control and injury groups received an equal volume of intralipid (vehicle solution of propofol) by ip injection. The dose of propofol was chosen based on our previous experiment18 as well as a study from another group that shows that administration of propofol 50 mg/kg ip inhibited rat hippocampal acetylcholine release to a lesser degree than propofol 100 mg/kg ip19, and produced a sedative response in rats, estimated as loss of reflex responses to a painful stimulus, while remaining sensitive to skin incision (i.e., sedation rather than anesthesia). By contrast, propofol 60 mg/kg ip, as reported by Brasil et al.,20 provided satisfactory anesthesia in rats. In addition, during our preliminary experiments, we found that neither ip intralipid (n = 4) or physiological saline (n = 3) influenced the extent of intestinal mucosal cell apoptosis in the injury group. Therefore, only intralipid was used as a vehicle control in the ensuing studies.

Preparation of Specimens
After the completion of the experiments, the rats were killed with an IV overdose of pentobarbital sodium. A segment of 0.5–1.0 cm intestine was cut from 5 cm to terminal ileum, fixed in 4% formaldehyde polymerisatum, and embedded in paraffin for preparation. Another segment of small intestine was washed with cold saline and the intestinal mucosa was gently scraped off, dried with suction paper, and preserved at –70°C.

Intestinal Mucosal Epithelial Apoptosis Detection under Transmission Electron Microscopy
The ileal segments were taken from a similar position in each rat and were fixed with phosphate-buffered glutaraldehyde (Ladd Research Industries, England), postfixed with osmium tetroxide (Prolabo, France) and then dehydrated, processed, sliced and observed under a Zeiss 902 electron microscope (Carl Zeiss, Thornwood, NY).

Situ Detection of Intestinal Mucosal Epithelial Apoptosis
The ileal fragments were fixed in 4% formaldehyde polymerisatum and embedded in paraffin. The apoptosis of intestinal mucosal epithelial cell was detected by the terminal deoxynucleotidyl transferase -mediated dUDP-biotin nick end labeling (TUNEL) method. Cell death was assessed using an assay kit (Roche, Indianapolis, IN). Briefly, specimens were dewaxed and immersed in phosphate-buffered saline containing 3 g/L hydrogen peroxide for 10 min at room temperature and then incubated with 20 µg/mL proteinase K for 15 min at room temperature. Equilibration buffer (75 µL) was applied directly onto the specimens for 10 min at room temperature, followed by incubation with 55 µL of terminal deoxynucleotidyl transferase enzyme at 37°C for 1 h. The reaction was terminated by transferring the slides to prewarmed stop/wash buffer for 30 min at 37°C. The specimens were covered with a few drops of rabbit serum and incubated for 20 min at room temperature and then covered with 55 µL of antidigoxigenin peroxidase and incubated for 30 min at room temperature. Specimens were then soaked in Tris buffer containing 0.2 g/L diaminobenzidine and 0.2 g/L hydrogen peroxide for 1 min for color development. Finally, the specimens were counterstained by immersion in hematoxylin. The cells with clear nuclear labeling were defined as TUNEL-positive cells. The apoptosis was initially evaluated independently by two pathologists who were blinded to the study groups. The rate of cell apoptosis (apoptotic index) was calculated as percentage of TUNEL-positive cells using the following formula: the number of TUNEL-positive cell nuclei/the number of total cell nuclei) x 100.

Detection of Lipid Peroxidation and Superoxide Dismutase (SOD) Activity in Intestinal Mucosa
Intestinal mucosal tissues were homogenized on ice with normal saline and centrifuged for 15 min at 4000g. Supernatants were transferred into fresh tubes for the evaluation. The lipid peroxidation product malonediadehyde (MDA) was measured by chemical analysis (Assay kits were supplied by Nanjing Jiancheng Biological Product, Nanjing, China) as previously described.21 The results were expressed as nanomoles per 100 mg tissue. SOD activity was evaluated by inhibition of nitroblue tetrazolium reduction by superoxide anion generated by the xanthine/xanthine oxidase system using a commercial assay kit (Nanjing Jiancheng Biological Product, Nanjing, China) as previously described.21 The results were expressed as Units per 100 mg protein.

Detection of Ceramide Level in Intestinal Mucosa
The ceramide level was determined by high performance thin layer chromatography as described by Dasgupta and Hogan.22 Tissue was homogenized with chloroform-methanol-water 2:4:1 (v/v/v; 14 mL/g of tissue), stirred for 1 h and centrifuged. The pellet was reextracted with the same solvent. A third extraction was performed with chloroform-methanol 2:1 (v/v). The extracts were pooled, dried, and suspended in a minimum volume of chloroform. The chloroform suspension was applied to a silicic acid column (0.5 x 5 cm) and washed with 15 column volumes of chloroform to remove nonpolar lipids (which can be assayed by TLC). The column was then eluted successively with chloroform-acetone 9:1 (v/v; 15 column volumes), and then dried and stored at 4°C until use. Ceramide, purified by silicic acid chromatography [chloroformacetone 9:1 (v/v)], was dissolved in a defined volume of chloroform (1.0 mL/g tissue) and 15 µL was applied to a high performance thin layer chromatography plate, developed with chloroform-methanol-acetic acid 95:4.5:0.5 (v/v/v) and visualized by benzidine spray. A measured volume (5 µL) of the ceramide solution was removed and methanolyzed with methanol-water-HCl 29:4:3 (v/v/v) at 80°C for 18 h, and the recovered base was analyzed by gas chromatography as the trimethylsilyl derivative. The recovery of the standard ceramide purified through the silicic acid column, using chloroform-acetone 9:1 (v/v), was more than 95%.

Detection of Neutral- Sphingomyelinase (SMase) mRNA Expression by Semi-Quantitative Reverse-Transcription Polymerase Chain Reaction (RT-PCR) in Intestinal Mucosa
The hydrolysis of sphingomyelin regulated by sphingomyelinase (SMase) is known as the main regulating mode of endogenous ceramide level.11,23 At least three kinds of SMase, including acid-SMase, neutral-SMase, and alkaline-SMase have been demonstrated to be involved in the generation of ceramide.24,25 It is reported that neutral SMase plays a more important role in the development of apoptosis relative to that of the acid-SMase and alkaline-SMase.26–29 Therefore, we only investigated the change of neutral SMase expression in the current study.

Total RNA was extracted from intestinal mucosal tissue using Trizol reagent (Gibco BRL, Gercy-Pontoise, France), cDNA was synthesized from 4 µg of the total RNA by extension of random primers with MMLV reverse transcriptase (Promega, Madison, WI). Polymerase Chain Reaction (PCR) of the cDNA was performed in a final volume of 25 µL containing 2 mM MgCl2, 4 Ues Taq DNA polymerase (Gibco BRL, Gercy-Pontoise, France), and 25 pmol specific primers. β-action was used as a control. The PCR was performed in the following conditions: denaturation for 3 min at 95°C, annealing for 30 s at 61°C for SMase and 62°C for β-actin, extension for 30 s at 72°C and for 35 cycles followed by further extension for 7 min at 72°C. Primer sequences were as follows: neutral-SMase, 5' TGA TGC CTT TGT TGA GAC CGA 3' (sense); 5' GGA AGC CAG AGA CTG CCT TGTA 3' (antisense); β-action, 5' AGC CAT GTA CGT AGC CAT CC-3' (sense); 5' GTC CAT GCA GTT CTT GGT CA 3' (antisense). The synthesized PCR products were separated by electrophoresis on a 20 g/L agarose gel and analyzed by Gel-Pro analyzer version 3.1 software (Media Cybernetics, GA). The ratio of target genes over β-actin was used for the relative level of mRNA expression.

Statistical Analysis
Results are expressed as mean ± sd. Biochemical assays for MDA, SOD, and ceramide were performed in duplicate or triplicate for each specific sample. Significance was evaluated using analysis of variance (GraphPad Prism 4, San Diego, CA) followed by Tukey's post test. The correlation relationships were evaluated by the Pearsons test. P < 0.05 was considered statistically significant.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Changes of Intestinal Mucosal Epithelial Apoptosis Under Transmission Electron Microscopy and Light Microscopy
No animals died in this experiment. Electron microscopy was used to confirm morphological features of cell apoptotic alterations. Figure 1A (control group) shows normal epithelial cells. Significant epithelial cell apoptosis in the intestinal mucosa, manifested by marked cytoplasm shrinkage, nuclear/chromatin condensation, and formation of apoptotic bodies, was seen in the injury group (Fig. 1B), This was attenuated by pretreatment with propofol (Fig. 1C). TUNEL-positive epithelial cells at the villus surface stained dark brown in the nuclei (Fig. 2). In the control group, few TUNEL-positive cells were found (Fig. 2A). In contrast, the apoptotic index was significantly higher in the injury group (Fig. 2B) than that in the control group (P < 0.01, Fig. 2D). However, pretreatment with propofol significantly suppressed apoptosis and reduced the apoptotic index, compared to the injury group (P < 0.01) as shown in Figures 2C and D.


Figure 121
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  		Figure 1. Changes of intestinal mucosal epithelial apoptosis under transmission electron microscopy. Rats either underwent a sham operation (control), 1 h occlusion of the superior mesenteric artery (SMA) followed by 3 h of reperfusion (injury), or received propofol pretreatment before 1 h occlusion of the SMA followed by 3 h of reperfusion (propofol). Arrows indicate normal intestinal mucosal epithelial cells in the control group (A, x6600), typical apoptotic intestinal mucosal epithelial cells in injury (B, x8900) and propofol (C, x8900) groups.

 

Figure 221
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  		Figure 2. Effect of propofol on intestinal mucosal cell apoptosis by light micrographs of the ileum stained using TUNEL assay (x200). Groups are the same as Figure 1. Apoptotic nuclei are stained dark brown indicated by arrows. (A) In the control group, few apoptotic epithelial cells were present at the villous tips. (B) In the injury group, quite a few apoptotic epithelial cells were seen. (C) In the propofol group, some apoptotic epithelial cells were seen, but the apoptotic index is significantly lower than that in the injury group (D). Data are mean ± sem *P < 0.01 versus control; #P < 0.01 versus injury. n = 10 rats per group.

 

Changes of the MDA Level and the Activity of SOD in Intestinal Mucosa
As shown in Figure 3A, the MDA level in the injury group was significantly higher than that in the control group (P < 0.01), and this was significantly reduced by pretreatment with propofol (P < 0.01, propofol group versus injury group).However, the SOD activity in the injury group was markedly reduced (P < 0.01, injury versus control group), but propofol significantly increased and restored SOD activity (P < 0.01, propofol versus injury or control, Fig. 3B).


Figure 321
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  		Figure 3. Effects of propofol on the malondialdehyde (MDA) level (A) and the superoxide dismutase (SOD) activity (B) in intestinal mucosa. Groups as in Figure 1.Data are mean ± sem *P < 0.01 versus control; #P < 0.01 versus injury. n = 10 rats per group.

 

Change of the Ceramide Level in Intestinal Mucosa
In the injury group, the ceramide level was significantly higher than that in the control group (P < 0.01). It was reduced by propofol pretreatment (P < 0.01, propofol versus injury, Fig. 4).


Figure 421
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  		Figure 4. Effect of propofol on the ceramide level in rat intestinal mucosa. Groups as in Figure 1. Data are mean ± sem *P < 0.01 versus control; #P < 0.01 versus injury. n = 10 rats per group.

 

Change of SMase mRNA Expression in Intestinal Mucosa
SMase mRNA expression was detectable in the control group and was significantly increased in the injury group (P < 0.01, injury versus control, Fig. 5). Compared to the injury group, SMase mRNA expression was markedly down-regulated in the propofol group (P < 0.01) to a level comparable to the control group (P > 0.05) (Fig. 5).


Figure 521
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  		Figure 5. Effect of propofol on the sphingomyelinase (SMase) mRNA expression in rat intestinal mucosa. Groups as in Figure 1. The SMase mRNA expression was analyzed by RT-PCR. The ratio of target genes over β-action was used for the relative level of mRNA expression (Top). In the injury group, SMase mRNA expression was significantly up-regulated (P < 0.01), but was markedly down-regulated in the propofol and control groups, as demonstrated in the bar graph (Bottom). The internal control gene (β-action) expression was almost the same level in the all samples. Data are mean ± sem *P < 0.01 versus control; #P < 0.01 versus injury. n = 10 rats per group.

 

Correlation Analysis
Overall (n = 30), the SMase mRNA expression was positively correlated to the MDA level (r = 0.554, P = 0.002, Fig. 6A), and negatively correlated to the SOD activity (r = –0.414, P = 0.023, Fig. 6B). In addition, strong positive correlations between the SMase mRNA expression and the ceramide level (r = 0.676, P = 0.000, Fig. 6C) and between the ceramide level and the apoptosis index (r = 0.849, P = 0.000, Fig. 6D) were identified.


Figure 621
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  		Figure 6. The scatter plots of correlative relationships between different parameters. (A) The malondialdehyde level and the sphingomyelinase (SMase) mRNA expression (r = 0.554, P = 0.002). (B) The superoxide dismutase (SOD) activity and the SMase mRNA expression (r = –0.414, P = 0.023). (C) The SMase mRNA expression and the ceramide level (r = 0.676, P < 0.0001). D. The ceramide level and the apoptosis index (r = 0.849, P < 0.0001).

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have demonstrated in a rat model that 1-h occlusion of the SMA followed by 3 h of reperfusion caused significant intestinal epithelial apoptosis in accordance with previous reports.4–6,9 The intestinal epithelial apoptosis induced by II/R was accompanied by dramatic increases in the intestinal mucosa of MDA, ceramide and SMase mRNA expression, and a decrease in SOD activity, confirming our recent study results conducted in the same model.9,18 The novel finding of the current study is that pretreatment with propofol, at a dose that has been shown to produce sedation in the rat,19 attenuated intestinal mucosal apoptosis induced by SMA occlusion and reperfusion. Apoptosis has been established as a major mode of intestinal mucosal cell death caused by II/R injury.4–6 Therefore, the protective effect of propofol on intestinal mucosal injury induced by II/R18 could be attributable, at least in part, to prevention of intestinal mucosal cell apoptosis.

It has been shown that ceramide is involved in the process of cellular apoptosis10 and the hydrolysis of sphingomyelin regulated by SMase is known as the main regulating mode of endogenous ceramide levels.11,23 The tight positive correlation between the apoptosis index and the ceramide level, as well as between the ceramide level and SMase mRNA expression in the present study, is in line with our recent study results in the same model,9 which supports ceramide as a mediator of apoptotic cell death in this model. The present findings showed that propofol pretreatment could down-regulate SMase mRNA expression and reduce ceramide production, which is another novel finding of the present study. The above findings suggest that the antiapoptotic effect of propofol is related to the ceramide-SMase pathway, although further study is needed to confirm a potential causative role that the ceramide-SMase pathway may have played in propofol-mediated protection.

In our understanding, the relationship between the SMase-ceramide pathway and propofol's effect against II/R-induced intestinal mucosal cell apoptosis may be explained as follows. First, studies showed that antioxidants can inhibit apoptosis by down-regulating neutral SMase expression and reducing ceramide production.26,27 The tight negative correlation between SOD activity and SMase mRNA expression and the significant positive correlation between MDA levels and SMase mRNA expression in the present study are, in fact, supportive of the concept that ROS are involved in mediating SMase expression. Also, in neuronal and vascular cells, ROS were reported to be critical in mediating the downstream effects of ceramide, including mitochondrial iron uptake, cytochrome c release, caspase 3 activation, and apoptosis.30 These findings indicate that ROS appear to interact with cell apoptosis processes mediated by the SMase-ceramide pathway in various tissues. Second, propofol is an excellent free radical scavenger that has been shown to enhance the antioxidative ability of various tissues both in vivo and in vitro studies.10,11 Of interest, propofol (50 mg/kg ip) increased SOD activity to a level higher than that in the control group (Fig. 3B). This result is similar to that reported by Zhu et al.31 They found that propofol at a clinically relevant low concentration (1 µM), but not at higher concentrations (>10 µM) increased SOD activity to a level higher than that in the control group in the primary cultured newborn rat hippocampus.31 The mechanism for this propofol effect is not clear, but it could be attributable to propofol's preconditioning-like effect as we described previously.15 Thus, the suppressive effect of propofol on ceramide production could be mainly attributable to this antioxidative property. Third, the effect of propofol on the SMase-ceramide pathway could be relevant to its effects on inflammatory cytokines. II/R can damage the intestinal barrier, which in turn causes the release of some proinflammatory cytokines such as tumor necrosis factor and interleukin-6.3,32 These proinflammatory mediators can stimulate the hydrolysis of sphingomyelin regulated by SMase, and thereby, increase the generation of ceramide.18 Thus, proinflammatory cytokines could serve as a link between II/R and the ceramide pathway. Studies have shown that propofol attenuates cytokine responses (tumor necrosis factor {alpha}, interleukin-6) to endotoxemia in vivo33–35 and in vitro.36 Taken together, the effect of propofol on the ceramide pathway may be related to its antioxidant property and inhibition of cytokine responses, although further study is needed to confirm this.

Our findings suggest that propofol is a promising drug for the prevention of II/R injury. However, it should be noted that our study may have several possible limitations. First, although propofol at 50 mg/kg ip, a sedative or subanesthetic dose, may not significantly affect cardiac functions, hemodynamic variables such as arterial blood pressure and cardiac output were not monitored. Therefore, we do not know whether propofol, at the dose used, could affect intestinal blood perfusion during postischemic intestinal reperfusion. Second, simultaneous detection of the expression of apoptosis-related genes and proteins, such as bcl-2, bax and caspase, should strengthen the mechanistic study and confirmation of apoptosis. However, the TUNEL method in combination with electron microscopy should be sufficient to confirm the existence of apoptosis, given that intestinal mucosal epithelial apoptosis induced by II/R in this model has been well-established by previous studies.4–6 Third, the ceramide signal pathway is very complex, but we only investigated its upstream events, such as oxidative stress and mRNA expression of netural-SMase. Therefore, whether downstream events in the ceramide pathway relevant to II/R-induced intestinal mucosal cell apoptosis are involved in propofol's antiapoptotic effect needs to be further investigated. Also, further studies should be conducted to investigate the propofol dose-response relationship with apoptosis on this model, which will provide more convincing evidence of a cause-effect relationship.

In conclusion, the present results indicate that pretreatment with a sedative dose of propofol attenuates intestinal epithelial apoptosis and this may be attributable to its antioxidant property in mediating the SMase-ceramide pathway. This finding is worthy of further clinical study in situations where propofol is an option for sedation and anesthesia in patients at risk of II/R.


   Footnotes
 
Accepted for publication May 7, 2008.

Supported, in part, by a grant from National Natural Science Foundation of China (No: 30672021, to K.X.L.).

The authors K.X.L. and Z.X. share senior authorship.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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