Role of interleukin 18 in acute lung inflammation induced by gut ischemia reperfusion

AIM: To study the changes of endogenous interleukin 18 (IL-18) levels and evaluate the role of IL-18 on lung injury following gut ischemia/reperfusion. METHODS: A superior mesenteric artery occlusion model was selected for this research. The mice were randomly divided into four groups: Sham operation (sham), ischemia (0.5 h) followed by different times of reperfusion (I/R), and I/R pretreated with exogenous IL-18 (I/R+IL-18) or IL-18 neutralizing antibody (I/R+IL-18Ab) 15 min before ischemia. Serum IL-18 levels were detected by Western blot and ELISA, and the levels of IL-18 in lung tissue were evaluated by immunohistochemical staining. For the study of pulmonary inflammation, the lung myeloperoxidase (MPO) contents and morphological changes were evaluated. RESULTS: Gut ischemia/reperfusion induced rapid increase of serum IL-18 levels, peaked at 1 h after reperfusion and then declined. The levels of IL-18 in lung tissue were gradually enhanced as the progress of reperfusion. Compared with I/R group, exogenous administration of IL-18 (I/R+IL-18) further remarkably enhanced the pulmonary MPO activity and inflammatory cell infiltration, and in I/R+IL-18Ab group, the content of MPO were significantly reduced and lung inflammation was also decreased. CONCLUSION: Gut ischemia/reperfusion induces the increase of IL-18 expression, which may make IL-18 act as an important proinflammatory cytokine and contribute to gut ischemia/reperfusion-induced lung inflammation.     

Protective effects of terminal ileostomy against bacterial translocation in a rat model of intestinal ischemia/reperfusion injury

AIM: To investigate the effects of terminal ileostomy on bacterial translocation (BT) and systemic inflammation after intestinal ischemia/reperfusion (I/R) injury in rats.METHODS: Thirty-two rats were assigned to either the sham-operated group, I/R group, I/R + resection and anastomosis group, or the I/R + ileostomy group. The superior mesenteric artery was occluded for 60 min. After 4 h, tissue samples were collected for analysis. BT was assessed by bacteriologic cultures, intestinal permeability and serum levels of endotoxin; systemic inflammation was assessed by serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10, as well as by the activity of myeloperoxidase (MPO) and by intestinal histopathology.RESULTS: Intestinal I/R injury not only caused morphologic damage to ileal mucosa, but also induced BT, increased MPO activity and promoted the release of TNF-α, IL-6, and IL-10 in serum. BT and ileal mucosa injuries were significantly improved and levels of TNF-α and IL-6 in serum were decreased in the I/R + ileostomy group compared with the I/R + resection and anastomosis group.CONCLUSION: Terminal ileostomy can prevent the detrimental effects of intestinal I/R injury on BT, intestinal tissue, and inflammation.     

Effect of nuclear factor kappa B on intercellular adhesion molecule-1 expression and neutrophil infiltration in lung injury induced by intestinal ischemia/reperfusion in rats

AIM:To investigate the role of nuclear factor kappa B(NF-κB) in the pathogenesis of lung injury induced byintestinal ischemia/reperfusion (I/R),and its effect onintercellular adhesion molecule-1 (ICAM-1) expressionand neutrophil infiltration.METHODS:Twenty-four Wistar rats weredivided randomly into control,I/R and pyrrolidinedithiocarbamate (PDTC) treatment groups,n=8 ineach.I/R group and PDTC treatment group receivedsuperior mysenteric artery (SMA) occluding for 1 h andreperfusion for 2 h.PDTC group was administrated withintraperitoneal injection of 2% 100 mg/kg PDTC 1 hbefore surgery.Lung histology and bronchia alveoluslung fluid (BALF) protein were assayed.Serum IL-6,lungmalondialdehyde (MDA) and myeloperoxidase (MPO) aswell as the expression level of NF-κB and ICAM-1 weremeasured.RESULTS:Lung injury induced by intestinal I/R,wascharacterized by edema,hemorrhage and neutrophilinfiltration as well as by the significant rising of BALFprotein.Compared to control group,the levels of serumIL-6 and lung MDA and MPO increased significantly in I/Rgroup (P=0.001).Strong positive expression of NF-κBp65 and ICAM-1 was observed.After the administrationof PDTC,the level of serum IL-6,lung MDA and MPOas well as NF-κB and ICAM-1 decreased significantly(P<0.05) when compared to I/R group. CONCLUSION:The activation of NF-kB plays animportant role in the pathogenesis of lung injury inducedby intestinal I/R through upregulating the neutrophilinfiltration and lung ICAM-1 expression.PDTC as aninhibitor of NF-kB can prevent lung injury induced byintestinal I/R through inhibiting the activity of NF-kB.     

Low-dose ethanol attenuates gut ischemia/reperfusion-induced liver injury in rats via nitric oxide production

BACKGROUND AND AIMS: The acute administration of low-dose ethanol was demonstrated to attenuate liver injury elicited by gut ischemia/reperfusion (I/R). Nitric oxide (NO) has been found to be a modulator of adhesive interactions between leukocytes, platelets, and endothelial cells, but there has been much controversy about the effects of ethanol on NO regulation. The objective of this study was to investigate the role of NO in ethanol-reduced hepatic microvascular dysfunction elicited by gut I/R. METHODS: Male Wistar rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor leukocyte recruitment and non-perfused sinusoids (NPS). Plasma alanine aminotransferase (ALT) activities were measured 6 h after the onset of reperfusion. In another set of experiments, ethanol (10%, 1 g/kg) was administered before ischemia. RESULTS: Gut I/R elicited increases in the number of stationary leukocytes, NPS, and plasma ALT activities; all of which were attenuated by pretreatment with ethanol or an NO donor. Gut I/R caused the apoptosis of hepatocytes, which was prevented by pretreatment with ethanol. Pretreatment with an NO synthase inhibitor diminished the protective effects of ethanol. The administration of ethanol increased plasma nitrite/nitrate levels. CONCLUSION: These results suggest that low-dose ethanol attenuates the gut I/R-induced hepatic microvascular dysfunction and sequential liver injury by increasing sinusoidal NO levels.     

Liver-lung interactions following Escherichia coli bacteremic sepsis and secondary hepatic ischemia/reperfusion injury

We hypothesized that ischemia/reperfusion (I/R) injury of the liver during normotensive gram-negative bacteremic sepsis alters the kinetics of circulating endotoxin, tumor necrosis factor-alpha (TNF-alpha), and coinduced mediators, thereby exacerbating sepsis-induced lung inflammation. Liver and lung dysfunction were studied after hematogenous infection of Sprague-Dawley rats with 10(9) Escherichia coli serotype O55:B5 (EC) and 90 min of secondary hepatic ischemia in EC + I/R and saline-infused (normal saline NS) x I/R rats, followed by brief (1 h) or longer reperfusion (24 h). TNF- alpha:leukotriene interactions in this model were examined using the 5-lipoxygenase-activating protein inhibitor MK-886. Compared with sham-operated EC + Sham animals, peak serum endotoxin, TNF-alpha, alanine aminotransferase, interleukin-6 (IL-6), and hepatic neutrophil (PMN) influx were higher in EC + I/R rats through 24 h (p < 0.05) despite comparable arterial pressure. Lung PMN influx and wet/dry weight ratios were likewise enhanced in EC + I/R versus EC + Sham or NS + I/R rats. MK-886 attenuated TNF-alpha concentrations and ischemic liver injury but not mortality. Thus, focal hepatic I/R augments circulating endotoxin, TNF-alpha, and postbacteremic lung inflammation early after normotensive E. coli bacteremic sepsis.     

抑制GSK-3β减轻大鼠急性心肌缺血/再灌注损伤的作用

目的:评估糖原合酶激酶-3β（GSK-3β）抑制剂TDZD-8减轻大鼠急性心肌缺血/再灌注损伤(MIRI)的作用,并探讨此作用是否与其下调NF-κB、抑制炎症有关。方法: 取健康雄性SD大鼠60只,随机分为缺血/再灌注(I/R)组、I/R+TDZD组、I/R+载体(Vehicle,V)组及假手术（Sham）组。大鼠局部心肌缺血30 min,再灌注3 h。用TTC染色计算心肌梗死面积,HE染色及ELISA法评估心肌组织中中性粒细胞浸润及炎性因子(TNF-α和IL-6)的变化;用Western blot测定心肌组织中NF-κB、GSK-3β磷酸化的水平。结果: TDZD-8能明显降低心肌梗死的面积和心肌组织中性粒细胞浸润、抑制NF-κB激活以及心肌源性TNF-α和IL-6的浓度(P<0.01)。结论: GSK-3β抑制剂TDZD-8能够减轻MIRI,其作用可能与其抑制NF-κB的激活及炎症反应有关。     

The influence of iloprost on acute lung injury induced by hind limb ischemia-reperfusion in rats

The local ischemia-reperfusion (I/R) process gains a systemic nature and affects distal organs. The remote effects of I/R are most frequently observed in the lungs and pulmonary damage may vary from acute lung injury with mild dysfunction to severe respiratory failure or the acute respiratory distress syndrome. In this hind limb I/R induced experimental lung injury model two groups of rats as IR and ILO were determined. Both groups underwent 60 min of ischemia and 120 min of reperfusion. While ILO group received iloprost in saline, IR group received only saline before reperfusion period intravenously. Serum myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels and total antioxidant capacity (TAC) and lung tissue MPO activity, MDA levels and Na+-K+ ATPase activity were measured and light microscopic analyses of lung specimens were performed. The MPO activities in serum and lung homogenates were found to be significantly decreased in ILO group (P < or = 0.01). The MDA levels in lung homogenates were found to be significantly decreased in ILO group (P < or = 0.01), but the decreases were not significant in serum MDA levels (P=0.052). Serum TAC and lung tissue Na+-K+ ATPase activity levels were found to be increased in ILO group compared to IR group (P < or = 0.01). Lung histology showed marked improvement by iloprost compared to the IR group in this study. Iloprost has been found to be effective in attenuating ischemia reperfusion-induced remote organ damage, in this case, lung injury, in rats.     

Glutamine prevents oxidative stress in a model of mesenteric ischemia and reperfusion

AIM: To evaluate preventative effects of glutamine in an animal model of gut ischemia/reperfusion (I/R).METHODS: Male Wistar rats were housed in a controlled environment and allowed access to food and water ad libitum. Twenty male Wistar rats were divided into four experimental groups: (1) control group (control) - rats underwent exploratory laparotomy; (2) control + glutamine group (control-GLU) - rats were subjected to laparotomy and treated intraperitoneally with glutamine 24 and 48 h prior to surgery; (3) I/R group - rats were subjected to occlusion of the superior mesenteric artery for 30 min followed by 15 min of reperfusion; and (4) ischemia/reperfusion + glutamine group (G + I/R) - rats were treated intraperitoneally with glutamine 24 and 48 h before I/R. Local and systemic injuries were determined by evaluating intestinal and lung segments for oxidative stress using lipid peroxidation and the activity of superoxide dismutase (SOD), interleukin-6 (IL-6) and nuclear factor kappa beta (NF-κB) after mesenteric I/R.RESULTS: Lipid peroxidation of the membrane was increased in the animals subjected to I/R (P < 0.05). However, the group that received glutamine 24 and 48 h before the I/R procedure showed levels of lipid peroxidation similar to the control groups (P < 0.05). The activity of the antioxidant enzyme SOD was decreased in the gut of animals subjected to I/R when compared with the control group of animals not subjected to I/R (P < 0.05). However, the group that received glutamine 24 and 48 h before I/R showed similar SOD activity to both control groups not subjected to I/R (P < 0.05). The mean area of NF-κB staining for each of the control groups was similar. The I/R group showed the largest area of staining for NF-κB. The G + I/R group had the second highest amount of staining, but the mean value was much lower than that of the I/R group (P < 0.05). For IL-6, control and control-GLU groups showed similar areas of staining. The I/R group contained the largest area of IL-6 staining, followed by the G + I/R animals; however, this area was significantly lower than that of the group that underwent I/R without glutamine (P < 0.05).CONCLUSION: These results demonstrate that pretreatment with glutamine prevents mucosal injury and improves gut and lung recovery after I/R injury in rats.     

Effect of nuclear factor kappa B on intercellular adhesionrnolecule-1 expression and neutrophil infiltration in lung injury induced by intestinal ischemia/reperfusion in rats

AIM: To investigate the role of nuclear factor kappa B(NF-κB) in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion (I/R), and its effect on intercellular adhesion molecule-1 (ICAM-1) expression and neutrophil infiltration.METHODS: Twenty-four Wistar rats were divided randomly into control, I/R and pyrrolidine dithiocarbamate (PDTC) treatment groups, n = 8 in each. I/R group and PDTC treatment group received superior mysenteric artery (SMA) occluding for 1 h and reperfusion for 2 h. PDTC group was administrated with intraperitoneal injection of 2% 100 mg/kg PDTC 1 h before surgery. Lung histology and bronchia alveolus lung fluid (BALF) protein were assayed. Serum IL-6, lung malondialdehyde (MDA) and myeloperoxidase (MPO) as well as the expression level of NF-κB and ICAM-1 were measured.RESULTS: Lung injury induced by intestinal I/R, was characterized by edema, hemorrhage and neutrophil infiltration as well as by the significant rising of BALF protein. Compared to control group, the levels of serum IL-6 and lung MDA and MPO increased significantly in I/R group (P=0.001). Strong positive expression of NF-κB p65 and ICAM-1 was observed. After the administration of PDTC, the level of serum IL-6, lung MDA and MPO as well as NF-κB and ICAM-1 decreased significantly(P＜ 0.05) when compared to I/R group.CONCLUSION: The activation of NF-κB plays an important role in the pathogenesis of lung injury induced by intestinal I/R through upregulating the neutrophil infiltration and lung ICAM-1 expression. PDTC as an inhibitor of NF-κB can prevent lung injury induced by intestinal I/R through inhibiting the activity of NF-κB.     

Effect of notoginsenoside R1 on hepatic microcirculation disturbance induced by gut ischemia and reperfusion

AIM： To assess the effect of notoginsenoside R1 on hepatic microcirculatory disturbance induced by gut ischemia/reperfusion （I/R） in mice. METHODS： The superior mesenteric artery （SMA） of C57/BL mice was ligated for 15 min to induce gut ischemia followed by 30-rain reperfusion. In another set of experiments, R1 was continuously infused （10 mg/kg per hour） from 10 min before I/R until the end of the investigation to study the influence of R1 on hepatic microcirculatory disturbance induced by gut I/R. Hepatic microcirculation was observed by inverted microscopy, and the vascular diameter, red blood cell （RBC） velocity and sinusoid perfusion were estimated. Leukocyte rolling and adhesion were observed under a laser confocal microscope. Thirty and 60 min after reperfusion, lactate dehydrogenase （LDH）, alanine aminotransferase （ALl＇） and aspartate transaminase （AST） in peripheral blood were determined. The expression of adhesion molecules CD11b/CD18 in neutrophils and tumor necrosis factor- alpha （TNF-α）, interleukin-6 （IL-6） and monocyte chemotactic protein-1 （MCP-1） in plasma were evaluated by flow Oltometry. E-selectin and intercellular adhesion molecule-1 （ICAM-1） in hepatic tissue were examined by immunofluorescence.RESULTS： After gut I/R, the diameters of terminal portal venules and central veins, RBC velocity and the number of perfused sinusoids were decreased, while the leukocyte rolling and adhesion, the expression of E-selectin in hepatic vessels and CD18 in neutrophils, IL-6, MCP-1, LDH, ALT and AST were increased. R1 treatment attenuated these alterations except for IL-6 and MCP-1. CONCLUSION： R1 prevents I/R-induced hepatic microcirculation disturbance and hepatocyte injury, The effect of R1 is related to its inhibition of leukocyte rolling and adhesion by inhibiting the expression of E-selectin in endothelium and CD18 in neutrophils.     

T-lymphocytes modulate the microvascular and inflammatory responses to intestinal ischemia-reperfusion

OBJECTIVE: The overall objective of this study was to define the contribution of T-lymphocytes to the microvascular and inflammatory responses of the intestine to ischemia/reperfusion (I/R). METHODS: The superior mesenteric artery of wild-type (WT) and SCID mice was occluded for 45 minutes, followed by 30 minutes or 6 hours of reperfusion. Intravital fluorescence microscopy was used to monitor the extravasation of FITC-labeled albumin or the adhesion of carboxy-fluorescein diacetate succinimidyl ester (CFSE)-labeled T-lymphocytes in mucosal venules of the postischemic intestine. Tissue myeloperoxidase (MPO) was used to monitor neutrophil accumulation in the intestine of WT and SCID mice. RESULTS: Although the number of adherent T-cells was not increased above baseline at 1 hour after reperfusion, significant T-cell adhesion (both CD4(+) and CD8(+)) was noted at 6 hours of reperfusion. The latter response was prevented by pretreatment with a blocking antibody directed against MAdCAM-1, but not ICAM-1 or VCAM-1. A significant increase in MAdCAM-1 expression was noted in both lymphoid (Peyer's patch) and nonlymphoid regions of the postischemic small bowel. The early (30 minutes after reperfusion) albumin extravasation elicited by gut I/R in WT mice was reduced in SCID mice. Reconstitution of SCID mice with T-lymphocytes restored the albumin leakage response to WT levels. The increased intestinal MPO caused by I/R (6 hours of reperfusion) in WT mice was attenuated in SCID mice; with reconstitution of SCID mice with T-cells the MPO response was restored. CONCLUSIONS: These findings indicate that intestinal I/R is associated with the recruitment of CD4+ and CD8+ T-cells, which is mediated by endothelial MAdCAM-1. T-cells seem to modulate the recruitment of neutrophils that occurs hours after reperfusion as well as the increased albumin extravasation that occurs within minutes after reperfusion.     

Effects of inhibition of PAF, ICAM-1 and PECAM-1 on gut barrier failure caused by intestinal ischemia and reperfusion

BACKGROUND: The role of cell adhesion molecules and transmigration of PMNs through the endothelial barrier is probably essential in intestinal ischemia and reperfusion (I/R)-induced gut barrier dysfunction. Although cytokines are released in I/R, it is unclear whether cytokines directly increase permeability or if this phenomenon requires both expression of cell adhesion molecules and PMN adhesion-activation. Endothelial barrier dysfunction plays an important role in the pathogenesis of multiple organ dysfunction syndrome, inducing gut barrier failure, but the mechanisms are not fully understood. The purpose of this study was to evaluate the potential therapeutic value of inhibition of platelet activating factor (PAF), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) in gut barrier dysfunction induced by intestinal I/R. METHODS: A PAF antagonist (lexipafant, BB-882) and monoclonal antibodies against rat ICAM-1 (anti-ICAM-1-MAb) and PECAM-1 (anti-PECAM-1-MAb) were used in a model of gut barrier dysfunction caused by intestinal ischemia for 40 min and concomitant reperfusion for 12 h in the rat, and endothelial permeability, myeloperoxidase activity, interleukin-1beta and protease inhibitor levels were evaluated. RESULTS: The endothelial permeability and tissue leukocyte recruitment in the distal small intestine significantly increased in rats with I/R treated with saline. Proteolytic activity in plasma was evident by low levels of the three measured plasma protease inhibitors. These changes were, to different degrees, reduced by treatment with lexipafant, anti-ICAM-1-MAb, or anti-PECAM-1-MAb. Alterations in systemic levels of interleukin-1beta paralleled the changes found in gut barrier permeability and leukocyte trapping. CONCLUSIONS: Our results suggest that treatment with the PAF inhibitor lexipafant and monoclonal antibodies against ICAM-1 or, seemingly most efficient, PECAM-1 reduces the severity of I/R-associated intestinal dysfunction, associated with a decrease in systemic concentrations of IL-1beta local leukocyte recruitment, and partly restoring plasma protease inhibitor levels.     

The type of sodium-coupled solute modulates small bowel mucosal injury,transport function,and ATP after ischemia/reperfusion injury in rats

BACKGROUND & AIMS: Gastrointestinal function may be impaired after severe injury, hampering tolerance to enteral nutrition. The purpose of this study was to determine how different sodium-coupled solutes modulate gut function after ischemia/reperfusion (I/R) in a rodent model. METHODS: At laparotomy, rats had jejunal sacs filled with (glucose + alanine), glucose, glutamine, alanine, or mannitol (osmotic control), followed by superior mesenteric artery clamping for 60 minutes and 30 minutes of reperfusion. After reperfusion, sacs were harvested for morphologic examination, adenosine triphosphate (ATP) assay, or mounted in an Ussing chamber. RESULTS: Small intestinal epithelial absorptive capacity, as assessed by changes in short-circuit current in response to glucose, after gut I/R, was decreased by alanine or (glucose + alanine) but not glucose or glutamine alone and correlated with changes in tissue ATP. Gut I/R caused a significant morphologic injury that was worsened by alanine or (glucose + alanine) but lessened by glucose or glutamine alone. CONCLUSIONS: During gut I/R, alanine can enhance gut injury, deplete energy (ATP), and impair gut absorption, whereas glucose or glutamine is protective against injury and can maintain absorptive capacity and ATP. These results suggest that solutes (such as alanine), which further stress an already metabolically stressed bowel, should be cautiously administered to critically ill patients whereas those solutes that contribute to energy production (such as glucose and glutamine) may be safely continued.     

Attenuation of reperfusion-induced systemic inflammation by preconditioning with nitric oxide in an in situ porcine model of normothermic lung ischemia

STUDY OBJECTIVES: Inhalation of nitric oxide (NO) can ameliorate pulmonary ischemia/reperfusion (I/R) injury of the lung in several experimental models, but toxic effects of NO were also reported. Here we investigate whether NO inhalation for a short period prior to surgery is sufficient to prevent symptoms of lung I/R injury, especially the inflammatory response. DESIGN: Using an in situ porcine lung model, normothermic left lung ischemia was maintained for 90 min, followed by a 5-h reperfusion period (group 1, n = 7). In group 2 (n = 6), I/R was preceded by inhalation of NO (10 min, 15 ppm). Animals in group 3 (n = 7) underwent sham surgery without NO inhalation or ischemia. MEASUREMENTS: Oxygenation and hemodynamic parameters were measured as indicators of lung functional impairment. Plasma levels of interleukin (IL)-1beta, IL-6, and transforming growth factor (TGF)-beta1 were determined throughout the I/R maneuver. In addition, tissue macrophages were analyzed by lectin binding. RESULTS: Symptoms of I/R injury (pulmonary hypertension and decreased oxygenation) in group 1 animals were attenuated by NO inhalation. The reperfusion-induced increases of the levels of IL-1beta and IL-6 in plasma were reduced by NO pretreatment. A peak of TGF-beta1 immediately after NO administration was observed in group 2, but not in groups 1 and 3. There was no significant effect of NO on tissue macrophages. CONCLUSION: NO inhalation for a short period prior to lung I/R is sufficient to protect against pulmonary hypertension, impaired oxygenation, and the inflammatory response of pulmonary I/R injury.     

Emodin alleviates lung ischemia–reperfusion injury by suppressing gasdermin D-mediated pyroptosis in rats

Background

Pyroptosis refers to programmed cell death associated with inflammation. Emodin has been reported to alleviate lung injuries caused by various pathological processes and attenuate ischemia–reperfusion (I/R) injuries in diverse tissues.

Methods

Lewis rats were assigned into the sham, the I/R, and the I/R + emodin groups. Emodin and phosphate-buffered saline were intraperitoneally injected into rats of the emodin group and I/R group for 30 min, respectively. These rats were then subjected to left thoracotomy followed by 90-min clamping of the left hilum and 120-min reperfusion. Sham-operated rats underwent 210-min ventilation. Lung functions, histological changes, lung edema, and cytokine levels were assessed. Protein levels were measured by western blotting. Immunofluorescence staining was conducted to evaluate pyroptosis.

Results

Emodin alleviated the I/R-induced lung dysfunction, lung damages, and inflammation. Protective effects of emodin against I/R-mediated endothelial pyroptosis was observed in vivo and in vitro. Mechanistically, emodin inactivated the TLR4/MyD88/NF-κB/NLRP3 pathway.

Conclusion

Emodin attenuates lung ischemia–reperfusion injury by inhibiting GSDMD-mediated pyroptosis in rats.     

Lansoprazole ameliorates intestinal mucosal damage induced by ischemia-reperfusion in rats

AIM:To investigate the protective effect of lansoprazoleon ischemia and reperfusion(I/R)-induced rat intestinalmucosal injury in vivo.METHODS:Intestinal damage was induced by clampingboth the superior mesenteric artery and the celiac trunkfor 30 rain followed by reperfusion in male Sprague-Dawleyrats.Lansoprazole was given to rats intraperitoneally 1 hbefore vascular clamping.RESULTS:Both the intraluminal hemoglobin and proteinlevels,as indices of mucosal damage,significantlyincreased in I/R-groups comparion with those of sham-operation groups.These increases in intraluminal hemoglobinand protein levels were significantly inhibited by the treatmentwith lansoprazole at a dose of 1 mg/kg.Small intestineexposed to I/R resulted in mucosal inflammation that wascharacterized by significant increases in thiobarbituric acid-reactive substances(TBARS),tissue-associatedmyeloperoxidase activity(MPO),and mucosal content of ratcytokine-induced neutrophil chemoattractant-1(CINC-1).These increases in TBARS,MPO activities and CINC-1 contentin the intestinal mucosa after I/R were all inhibited bypretreatment with lansoprazole at a dose of 1 mg/kg.Furthermore,the CINC-1 mRNA expression was increasedduring intestinal I/R,and this increase in mRNA expressionwas inhibited by treatment with lansoprazole.CONCLUSION:Lansoprazole inhibits lipid peroxidation andreduces development of intestinal mucosal inflammationinduced by I/R in rats,suggesting that lansoprazole mayhave a therapeutic potential for I/R injury.     

Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes

AIM： To investigate the hypothesis that the protective effects of curcumin in hepatic warm ischemia/reperfusion （I/R） injury are associated with increasing heat shock protein 70 （Hsp70） expression and antioxidant enzyme activity. METHODS： Sixty Sprague-Dawley male rats were randomly divided into sham, I/R, C ＋ I/R groups. The model of reduced-size liver warm ischemia and reperfusion was used. Curcumin （50 mg/kg） was administered by injection through a branch of superior mesenteric vein at 30 min before ischemia in C ＋ I/R group. Five rats were used to investigate the survival during 1 wk after operation in each group. Blood samples and liver tissues were obtained in the remaining animals after 3, 12, and 24 h of reperfusion to assess serum alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, liver tissue NO2- ＋ NO3-, malondialdehyde （MDA） content, superoxide dismutase （SOD）, catalase （CAT）, nitricoxide synthase （NOS） and myeloperoxidase （MPO） activity, HspT0 expression and apoptosis ratio. RESULTS： Compared with I/R group, curcumin pretreatment group showed less ischemia/reperfusioninduced injury. CAT and SOD activity and Hsp70 expression increased significantly. A higher rate of apoptosis was observed in I/R group than in C ＋ I/R group, and a significant increase of MDA, NO2^- ＋ NO3^- and MPO level in liver tissues and serum transaminase concentration was also observed in I/R group compared to C ＋ I/R group. Curcumin also decreased the activity of inducible NO synthase （iNOS） in liver after reperfusion,but had no effect on the level of endothelial NO synthase （eNOS） after reperfusion in liver. The 7 d survival rate was significantly higher in C ＋ I/R group than in I/R group. CONCLUSION： Curcumin has protective effects against hepatic I/R injury. Its mechanism might be related to the overexpression of Hsp70 and antioxidant enzymes.     

Lansoprazole ameliorates intestinal mucosal damage induced by ischemia-reperfusion in rats

AIM: To investigate the protective effect of lansoprazole on ischemia and reperfusion (I/R)-induced rat intestinal mucosal injury in vivo. METHODS: Intestinal damage was induced by clamping both the superior mesenteric artery and the celiac trunk for 30 min followed by reperfusion in male Sprague-Dawley rats. Lansoprazole was given to rats intraperitoneally 1 h before vascular clamping. RESULTS: Both the intraluminal hemoglobin and protein levels, as indices of mucosal damage, significantly increased in I/R-groups comparison with those of sham-operation groups. These increases in intraluminal hemoglobin and protein levels were significantly inhibited by the treatment with lansoprazole at a dose of 1 mg/kg. Small intestine exposed to I/R resulted in mucosal inflammation that was characterized by significant increases in thiobarbituric acid-reactive substances (TBARS), tissue-associated myeloperoxidase activity (MPO), and mucosal content of rat cytokine-induced neutrophil chemoattractant-1 (CINC-1). These increases in TBARS, MPO activities and CINC-1 content in the intestinal mucosa after I/R were all inhibited by pretreatment with lansoprazole at a dose of 1 mg/kg. Furthermore, the CINC-1 mRNA expression was increased during intestinal I/R, and this increase in mRNA expression was inhibited by treatment with lansoprazole. CONCLUSION: Lansoprazole inhibits lipid peroxidation and reduces development of intestinal mucosal inflammation induced by I/R in rats, suggesting that lansoprazole may have a therapeutic potential for I/R injury.     

Prophylaxis with carnosol attenuates liver injury induced by intestinal ischemia/reperfusion

AIM： To investigate the possible protective effects of carnosol on liver injury induced by intestinal ischemia reperfusion （I/R）.
METHODS： Rats were divided randomly into three experimental groups： sham, intestinal I/R and carnosol treatment （n = 18 each）. The intestinal I/R model was established by clamping the superior mesenteric artery for 1 h. In the carnosol treatment group, surgery was performed as in the intestinal I/R group, with intraperitoneal administration of 3 mg/kg carnosol 1 h before the operation. At 2, 4 and 6 h after reperfusion, rats were killed and blood, intestine and liver tissue samples were obtained. Intestine and liver histology was investigated. Serum levels of aspartate aminotransferase （AST）, alanine aminotransferase （ALT） and interleukin （IL）-6 were measured. Liver tissue superoxide dismutase （SOD） and myeloperoxidase （IvIPO） activity were assayed. The liver intercellular adhesion molecule-1 （ICAM-1） and nuclear factor κB （NF-κB） were determined by immunohistochemical analysis and western blot analysis.
RESULTS： Intestinal I/R induced intestine and liver injury, characterized by histological changes, as well as a significant increase in serum AST and ALT levels. The activity of SOD in the liver tissue decreased after I/R, which was enhanced by carnosol pretreatment. In addition, compared with the control group, carnosol markedly reduced liver tissue MPO activity and serum IL-6 level, which was in parallel with the decreased level of liver ICAI-1 and NF-κB expression.
CONCLUSION： Our results indicate that carnosol pretreatment attenuates liver injury induced by intestinal I/R, attributable to the antioxidant effect and inhibition of the NF-κB pathway.