• The Korean Journal of Physiology and Pharmacology
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• 제3권3호
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• pp.263-273
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• 1999

The role of phospholipase $A_2\;(PLA_2)$ in acute lung leak induced by intestinal ischemia was investigated in association with neutrophilic respiratory burst. To induce lung leak, we generated intestinal ischemia for 60 min prior to the 120 min reperfusion by clamping superior mesenteric artery in Sprague-Dawley rats. Acute lung leak was confirmed by the increased lung leak index and protein content in bronchoalveolar fluid. These changes were inhibited by mepacrine, the non-specific $PLA_2$ inhibitor. The lung myeloperoxidase (MPO) activity denoting the pulmonary recruitment of neutrophils was increased by intestinal I/R, but decreased by mepacrine. Simultaneously, the number of leukocytes in bronchoalveolar fluid was increased by intestinal ischemia/reperfusion (I/R) and decreased by mepacrine. Gamma glutamyl transferase activity, an index of oxidative stress in the lung, was increased after intestinal I/R but decreased by mepacrine, which implicates that $PLA_2$ increases oxidative stress caused by intestinal I/R. The $PLA_2$ activity was increased after intestinal I/R not only in the intestine but also in the lung. These changes were diminished by mepacrine. In the cytochemical electron microscopy to detect hydrogen peroxide, intestinal I/R increased the generation of the hydrogen peroxide in the lung as well as in the intestine. Expression of interleukin-1 (IL-1) in the lung was investigated through RT-PCR. The expression of IL-1 after intestinal I/R was enhanced, and again, the inhibition of $PLA_2$ suppressed the expression of IL-1 in the lung. Taken together, intestinal I/R seems to induce acute lung leak through the activation of $PLA_2$, the increase of IL-1 expression associated with increased oxidative stress by neutrophilic respiratory burst.

• The Korean Journal of Physiology and Pharmacology
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• 제3권6호
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• pp.579-586
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• 1999

Complement-mediated neutrophil activation has been hypothesized to be an important mechanism of reperfusion injury. It has been proposed that C1 esterase inhibitor (C1 INH) may prevent the complement- dependent activation of polymorphonuclear leukocytes (PMNs) that occurs within postischemic myocardium. Therefore, The effect of C1 INH was examined in neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of C1 INH (5 mg/Kg) to I/R hearts in the presence of PMNs $(100{\times}10^6)$ and homologous plasma improved coronary flow and preserved cardiac contractile function (p＜0.001) in comparison to those I/R hearts receiving only vehicle. In addition, C1 INH significantly (p＜0.001) reduced PMN accumulation in the ischemic myocardium as evidenced by an attenuation in myeloperoxidase activity. These findings demonstrate the C1 INH is a potent and effective cardioprotective agent inhibits leukocyte-endothelial interaction and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion.

• Archives of Pharmacal Research
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• 제22권5호
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• pp.479-484
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• 1999

In this study, the effects of ursodeoxycholic acid (UDCA) on ischemia/reperfusion injury were investigated on isolated heart perfusion model. Hearts were perfused with oxygenated Krebs-Henseleit solution (pH 7.4, $37^{\circ}C$) on a Langendroff apparatus. After equilibration, isolated hearts were treated with UDCA 20 to 160 $\mu$M or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. After global ischemia (30 min), ischemic hearts were reperfused and allowed to recover for 30 min. The physiological (i.e. heart rate, left ventricular developed pressure, coronary flow, double product and time to contracture formation) and biochemical (lactate dehydrogenase; LDH) parameters were evaluated. In vehicle-treated group, time to contracture formation was 21.4 min during ischemia, LVDP was 18.5 mmHg at the endpoint or reperfusion and LDH activity in total reperfusion effluent was 54.0 U/L. Cardioprotective effects of UDCA against ischemia/reperfusion consisted of a reduced TTC $(EC_{25}=97.3{\mu}M)$, reduced LDH release and enhanced recovery of cardiac contractile function during reperfusion. Especially, the treatments of UDCA 80 and $160 {\mu}M $ significantly increased LVDP and reduced LDH release. Our findings suggest that UDCA ameliorates ischemia/reperfusion-induced myocardial damage.

• 대한의생명과학회지
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• 제16권4호
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• pp.359-363
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• 2010

The miniature pig is a very suitable donor species in xenotransplantation of human organs. Intestine ischemia/reperfusion (I/R) is associated with high morbidity and mortality. Endoplasmic reticulum (ER) stress and apoptosis has been associated with the onset of diverse diseases. Thus, we examined the effect of intestine I/R on the expression of ER stress and apotptosis related molecules. In the present study, I/R induced phosphorylation of protein kinase-like endoplasmic reticulum kinase (PERK), IRE, and ATF-4. I/R also increased the expression of the proapoptotic transcription factor CAAT/enhancer-binding protein homologous protein (CHOP). In addition, I/R decreased the expression of Bcl-2, but increased the expression of Bax, cleaved PARP, and cleaved caspase-3. Moreover, I/R increased splicing form of XBP-1 mRNA and the expression of caspase-6 and caspase-3 mRNA. In conclusion, intestine I/R induced ER stress and apoptosis in miniature pig.

• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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• pp.181-187
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• 2009

Intestinal ischemia/reperfusion (I/R) is one of common causes of acute lung injury (ALI). Early and accurate diagnosis of patients who are like to develop serious acute respiratory distress syndrome (ARDS) would give a therapeutic advantage. Ferritin and heme oxygenase-1 (HO-1) are increased by oxidative stress and are potential candidates as a predictive biomarker of ARDS. However, the mechanisms responsible for the increases of ferritin and HO-1, and their relationship to ALI, are unclear. In order to elucidate the interactions between ferritin and HO-1, we studied the changes in ferritin and HO-1 levels in serum and bronchoalveolar lavage (BAL) fluid after intestinal I/R injury in rats. Leukocyte number and protein contents in BAL fluid were elevated following I/R, and the increases were attenuated by mepacrine pretreatment. Both serum ferritin and HO-1 concentrations were progressively elevated throughout the 3 h observation period. Mepacrine pretreatment attenuated the increase of serum and BAL fluid ferritin concentrations, but did not suppress the increase of serum HO-1. Moreover, BAL fluid HO-1 levels did not change after I/R or after mepacrine pretreated I/R compared with sham rats. Unlike ferritin, HO-1 levels are not exactly matched with the ALI. Therefore, there might be a different mechanism between the changes of ferritin and HO-1 in intestinal I/R-induced ALI model.

• The Korean Journal of Physiology and Pharmacology
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• 제23권5호
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• pp.329-334
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• 2019

Diabetes is associated with an increased risk of cardiovascular complications. Dipeptidyl peptidase-4 (DPP-IV) inhibitors are used clinically to reduce high blood glucose levels as an antidiabetic agent. However, the effect of the DPP-IV inhibitor gemigliptin on ischemia/reperfusion (I/R)-induced myocardial injury and hypertension is unknown. In this study, we assessed the effects and mechanisms of gemigliptin in rat models of myocardial I/R injury and spontaneous hypertension. Gemigliptin (20 and 100 mg/kg/d) or vehicle was administered intragastrically to Sprague-Dawley rats for 4 weeks before induction of I/R injury. Gemigliptin exerted a preventive effect on I/R injury by improving hemodynamic function and reducing infarct size compared to the vehicle control group. Moreover, administration of gemigliptin (0.03% and 0.15%) powder in food for 4 weeks reversed hypertrophy and improved diastolic function in spontaneously hypertensive rats. We report here a novel effect of the gemigliptin on I/R injury and hypertension.

• 대한본초학회지
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• 제28권3호
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• pp.7-15
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• 2013

Objectives : Interruption and subsequent restoration of blood flow into the kidney result in renal injury. As an approach to preventing the renal injury, we determined the optimal conditions and the underlying mechanisms by which supernatant of hot water extract of ground Triticum aestivum L. (extract) attenuated ischemia/reperfusion (I/R) injury. Methods : One hour after administration of the extract (400 mg/kg) by intraperitoneal injection, renal I/R injury was generated by clamping the left renal artery in rats after surgical removal of the right kidney, followed by reperfusion. The maximal difference between the vehicle-treated and the extract-treated group under ketamine/xylazine or enflurane anesthetization was assessed at varying periods of ischemia (30-45 min) and reperfusion (3-48 hr), based on the renal function assessed with serum creatinine levels, tissue injury with hematoxylin/eosin staining, and apoptosis with terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling staining. Results : Enflurane anesthetization with 40 min of ischemia and 24 hr of reperfusion was identified to be the optimal condition, under which condition serum creatinine levels and tubular damage in the extract-treated group were significantly reduced compared with those in the vehicle-treated group ($1.3{\pm}0.2$ versus $2.7{\pm}0.3$ mg/dL, P < 0.01, and average score $1.8{\pm}0.1$ versus $3.5{\pm}0.3$, P < 0.01, respectively). These beneficial effects were mediated by inhibition of apoptotic cascades through attenuation of renal tissue malondialdehyde levels, Bax/Bcl-2 ratio and caspase-3 levels. Conclusions : The extract conferred renal protection against ischemia/reperfusion injury in rats by scavenging reactive oxygen species and consequently blocking apoptotic cascades, plausibly augmented by enflurane protection.

• 한국임상수의학회지
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• 제25권3호
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• pp.165-169
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• 2008

Renal ischemia-reperfusion (I/R) injury is great clinical important because viability of the organ depends on the tolerance to ischemia-reperfusion injury, an inevitable processing during surgery. The purpose of this study was to investigate the effects of premedicated ascorbic acid alone in I/R injury model induced by cross-clamping of renal vessels. In the rabbit models, 2-4 kg New Zealand white rabbits were subjected to 30 minutes of warm unilateral renal ischemia followed by removal of contralateral kidney and then divided into five groups, control (2) arid treatment groups (3). In control group 1, the rabbits only received right nephrectomy. In control group 2, the rabbits received I/R on left kidney after the right nephrectomy. In treatment group 1, the rabbits received ascorbic acid 50 mg/kg IV before the operation. In treatment group 2, the rabbits received ascorbic acid 100 mg/kg IV before the operation. In treatment group 3, the rabbits received ascorbic acid 200 mg/kg IV before the operation. Blood samples were collected from these rabbits for measurement of kidney function tests at the 0, 1 st, 3rd and 7th day and antioxidant enzyme( SOD, GSHPx, CAT) at 24 hours. Kidney function tests (serum creatinine and BUN) showed a significant difference between group 2 and group 4, 5. Activity of antioxidant enzymes in plasma were significant decrease in group 4, 5 compare to group 2. The result of this study suggested that the exogenous ascorbic acid had a role of attenuation of renal I/R injury in rabbit model.

• The Korean Journal of Physiology and Pharmacology
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• 제15권5호
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• pp.259-266
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• 2011

The aim of this study was to evaluate the preventive role of epigallocatechin-3 gallate (EGCG, a derivative of green tea) in ischemia/reperfusion (I/R) injury of isolated rat hearts. It has been suggested that EGCG has beneficial health effects, including prevention of cancer and heart disease, and it is also a potent antioxidant. Rat hearts were subjected to 20 min of normoxia, 20 min of zero-flow ischemia and then 50 min of reperfusion. EGCG was perfused 10 min before ischemia and during the whole reperfusion period. EGCG significantly increased left ventricular developed pressure (LVDP) and increased maximum positive and negative dP/dt (+/-dP/dtmax). EGCG also significantly increased the coronary flow (CF) at baseline before ischemia and at the onset of the reperfusion period. Moreover, EGCG decreased left ventricular end diastolic pressure (LVEDP). This study showed that lipid peroxydation was inhibited and Mn-SOD and catalase expressions were increased in the presence of EGCG. In addition, EGCG increased levels of Bcl-2, Mn-superoxide dismutase (SOD), and catalase expression and decreased levels of Bax and increased the ratio of Bcl-2/Bax in isolated rat hearts. Cleaved caspase-3 was decreased after EGCG treatment. EGCG markedly decreased the infarct size while attenuating the increase in lactate dehydrogenase (LDH) levels in the effluent. In summary, we suggest that EGCG has a protective effect on I/R-associated hemodynamic alteration and injury by acting as an antioxidant and anti-apoptotic agent in one.

• The Korean Journal of Physiology and Pharmacology
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• 제27권3호
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• pp.257-265
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• 2023

Kidney ischemia/reperfusion (I/R) injury, a common cause of acute kidney injury (AKI), is associated with the migration of inflammatory cells into the kidney. Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho family of small GTPase, plays an important role in inflammatory cell migration by cytoskeleton rearrangement. Here, we investigated the role of Rac1 on kidney I/R injury and macrophage migration. Male mice were subjected to either 25 min of bilateral ischemia followed by reperfusion (I/R) or a sham operation. Some mice were administrated with either NSC23766, an inhibitor of Rac1, or 0.9% NaCl (vehicle). Kidney damage and Rac1 activity and expression were measured. The migration and lamellipodia formation of RAW264.7 cells, mouse monocyte/macrophage, induced by monocyte chemoattractant protein-1 (MCP-1, a chemokine) were determined using transwell migration assay and phalloidin staining, respectively. In sham-operated kidneys, Rac1 was expressed in tubular cells and interstitial cells. In I/R-injured kidneys, Rac1 expression was decreased in tubule cells in correlation with the damage of tubular cells, whereas Rac1 expression increased in the interstitium in correlation with an increased population of F4/80 cells, monocytes/macrophages. I/R increased Rac1 activity without changing total Rac1 expression in the whole kidney lysates. NSC23766 administration blocked Rac1 activation and protected the kidney against I/R-induced kidney damage and interstitial F4/80 cell increase. NSC23766 suppressed monocyte MCP-1-induced lamellipodia and filopodia formation and migration of RAW 264.7 cells. These results indicate Rac1 inhibition protects the kidney against I/R via inhibition of monocytes/macrophages migration into the kidney.