• 대한약리학회지
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• 제29권1호
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• pp.1-8
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• 1993

뇌의 허혈-재관류 손상에 있어서 혈소판 활성인자 (PAF, platelet activating factor)의 관련을 증명하기 위하여 흰쥐와 생쥐에서 양측 총경동맥을 10분간 결찰하고 그후 6시간동안 재관류시켜 허혈-재관류 손상을 야기시켰다. 생쥐에 PAF 길항제인 BN52021과 CV6209 (각각 1 mg/kg, i.p.)를 총경동맥결찰 10분전 또는 재관류 시작 1시간 후에 투여시 McGram stroke index는 심하게 억제되었다. 흰쥐와 생쥐에서 뇌허혈-재관류에 의한 뇌수분함량의 증가는 BN52021 또는 CV6209 전처치에 의하여 유의하게 억제되었다. BN52021 전처치는 허혈 후의 혈압변동을 개선시켰을 뿐만 아니라 뇌연막동맥의 확장지연에 대하여도 효과가 있었다. 이러한 실험결과로 보아 PAF가 뇌허혈-재관류 손상의 발생에 내인성 인자로서 중요한 역할을 하는 것으로 사료된다. 나아가 PAF 길항제가 뇌허혈후의 병리학적 후휴증의 개선 내지는 예방에 사용 될 수 있을 것으로 기대된다.

• Journal of Chest Surgery
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• 제32권7호
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• pp.637-647
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• 1999

배경: 여러 장기의 생체 내 혹은 생체 외 실험에서 삼요드티로닌(triiodothyronine; T3)이 장기의 허혈-재관류 손상을 줄이는 효과가 있을 것으로 보고되고 있다. 이 연구에서는 삼요드티로닌을 투여하여 폐장 이식 초기 에 이식 실패의 가장 중요한 원인인 폐장 허혈-재관류 손상을 줄일 수 있을 것으로 가정하고 폐 허혈-재관류 손상을 평가할 수 있는 동물 실험 모델을 통하여 이를 증명하고자 하였다. 대상 및 방법: 체중 15~20 kg의 잡견 16마리를 무작위로 두 군으로 나눈 뒤, 대조군인 A군에는 식염 수를 정맥 주사하고 실험군인 B군에는 일측 폐 허혈 유발 전에 삼요드티로닌 $3.6\mu$g/kg을 정맥 주사하였으며 주사량 (ml)은 두 군에서 같게 하였다. 좌측 폐문부를 차단하여 좌측 폐 허혈을 100분간 유발시킨 후 재관류시켰고, 재관류 후 4시간 동안 우측 폐문부를 간헐적으로 차단하면서 좌측 폐의 가스 교환능, 혈역학적 변수, 호흡 역학적 변수를 측정하였다. 실 험 종료 후 폐 조직 일부를 생검하여 폐 조직 수분 함량, 지방 산화물(malonedialdehide; MDA)과 조직 내 ATP양을 측정하고, 광학 현미경 소견을 관찰하였다. 결과: 동맥혈 산소 분압은 두 군에서 모두 재관류 30분에 감소하였다가 서서히 회복하는 양상을 보였으며 재관류 30분에 A군은 $125\pm34$ mmHg, B군은 $252\pm44$ mmHg, 실험을 종료한 4시간에 A군은 $178\pm42$ mmHg, B군은 $330\pm37$ mmHg으로 전 과정을 통해 실험군인 B군에서 내내 높았다(p<0.05). 동맥혈 이산화탄소 분압, 폐혈관 저항, 기관내압 및 폐 탄성도 등 호흡 역학적 변수, 그리고 폐 조직 수분 함량은 두 군간에 차이가 없었다. 조직 내 MDA양은 A군$(0.53\pm0.05mu$M)에 비해 B군$(0.40\pm0.04\mu$M)에서 낮았다 (p<0.05). ATP양은 A군에서$0.48\pm0.07\mu$M/g, B군에서 $0.69\pm0.07\mu$M/g으로 B군에서 높았다(p<0.05). 폐 생검 조직의 광학 현미경 소견은 혈관 주위 호중구 침윤, 모세 혈관 출혈과 간질 내 울혈 등이 관찰되었고 두 군간의 차이는 없었다. 결론: 이상의 결과에서 삼요드티로닌이 폐장의 허혈-재관류 손상 후 산소 교환능을 개선시키고, 조직 내 지방 산화물의 생성을 줄이며 조직 ATP를 증가시킴으로써 이식폐 보존에 유용하게 이용될 수 있음을 입증하였다.

• The Korean Journal of Physiology and Pharmacology
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• 제17권2호
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• pp.169-173
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• 2013

Renal ischemia-reperfusion (IR) causes remote liver damage. Oxytocin has anti-inflammatory and antioxidant effects. The main purpose of this study was to evaluate the protective function of oxytocin (OT) in remote liver damage triggered by renal IR in rats. Twenty four rats were randomly divided into four different groups, each containing 8 rats. The groups were as follows: (1) Sham operated group; (2) Sham operated+OT group (3) Renal IR group; (4) Renal IR+OT group. OT ($500{\mu}g/kg$) was administered subcutaneously 12 and 24 hours before and immediately after ischemia. At the end of experimental procedure, the rats were sacrificed, and liver specimens were taken for histological assessment or determination of malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), paraoxonase (PON-1) activity and nitric oxide (NO). The results showed that renal IR injury constituted a notable elevation in MDA, TOS, Oxidative stress index (OSI) and significantly decreased TAS, PON-1 actvity and NO in liver tissue (p<0.05). Additionally renal IR provoked significant augmentation in hepatic microscopic damage scores. However, alterations in these biochemical and histopathological indices due to IR injury were attenuated by OT treatment (p<0.05). These findings show that OT ameliorates remote liver damage triggered by renal ischemia-reperfusion and this preservation involves suppression of inflammation and regulation of oxidant-antioxidant status.

• Journal of Ginseng Research
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• 제40권2호
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• pp.196-202
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• 2016

Background: Ginsenoside Rd (GSRd), a main component of the root of Panax ginseng, exhibits anti-inflammation functions and decreases infarct size in many injuries and ischemia diseases such as focal cerebral ischemia. M1 Macrophages are regarded as one of the key inflammatory cells having functions for disease progression. Methods: To investigate the effect of GSRd on renal ischemia/reperfusion injury (IRI) and macrophage functional status, and their regulatory role on mouse polarized macrophages in vitro, GSRd (10-100 mg/kg) and vehicle were applied to mice 30 min before renal IRI modeling. Renal functions were reflected by blood serum creatinine and blood urea nitrogen level and histopathological examination. M1 polarized macrophages infiltration was identified by flow cytometry analysis and immunofluorescence staining with $CD11b^+$, $iNOS^+$/interleukin-12/tumor necrosis factor-${\alpha}$ labeling. For the in vitro study, GSRd ($10-100{\mu}g/mL$) and vehicle were added in the culture medium of M1 macrophages to assess their regulatory function on polarization phenotype. Results: In vivo data showed a protective role of GSRd at 50 mg/kg on Day 3. Serum level of serum creatinine and blood urea nitrogen significantly dropped compared with other groups. Reduced renal tissue damage and M1 macrophage infiltration showed on hematoxylin-eosin staining and flow cytometry and immunofluorescence staining confirmed this improvement. With GSRd administration, in vitro cultured M1 macrophages secreted less inflammatory cytokines such as interleukin-12 and tumor necrosis factor-${\alpha}$. Furthermore, macrophage polarization-related pancake-like morphology gradually changed along with increasing concentration of GSRd in the medium. Conclusion: These findings demonstrate that GSRd possess a protective function against renal ischemia/reperfusion injury via downregulating M1 macrophage polarization.

• The Korean Journal of Physiology and Pharmacology
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• 제2권3호
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• pp.331-343
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• 1998

Sublethal dose of bacterial lipopolysaccharide (LPS) would induce protection against cardiac ischemic/reperfusion (I/R) injury. This study examines the following areas: 1) the temporal induction of the cardio-protection produced by LPS; and 2) the relations between a degree of protection and the myocardial prostacyclin ($PGI_2$) production. Rats were administered LPS (2 mg/kg, i.v.), and hearts were removed 1, 4, 8, 14, 24, 48, 72,and 96 h later. Using Langendorff apparatus, haemodynamic differences during 25 min of global ischemia/30 min reperfusion were investigated. The concentration of $PGI_2$ in aliquots of the coronary effluent was determined by radioimmunoassay as its stable hydrolysis product $6-keto-PGF1_{\alpha}$ and lactate dehydrogenase release were measured as an indicative of cellular injury. LPS-induced cardiac protection against I/R injury appeared 4 h after LPS treatment and remained until 96 h after treatment. $PGI_2$ release increased 2-3 fold at the beginning of reperfusion compared to basal level except in hearts treated with LPS for 48 and 72 h. In hearts removed 48 and 72 h after LPS treatment, basal $PGI_2$ was increased. To determine the enzymatic step in relation to LPS-induced basal $PGI_2$ production, we examined prostaglandin H synthase (PGHS) protein expression, a rate limiting enzyme of prostaglandin production, by using Western blot analysis. LPS increased PGHS protein expression in hearts at 24, 48, 72, 96 h after LPS treatment. Induction of PGHS expression appeared in both isotypes of PGHS, a constitutive PGHS-1 and an inducible PGHS-2. To identify the correlationship between $PGI_2$ production and the cardioprotective effect against I/R injury, indomethacin was administered in vivo or in vitro. Indomethacin did not inhibit LPS-induced cardioprotection, which was not affected by the duration of LPS treatment. Taken together, our results suggest that $PGI_2$ might not be the major endogenous mediator of LPS-induced cardioprotection.

• Archives of Reconstructive Microsurgery
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• 제14권2호
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• pp.85-94
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• 2005

Purpose: This study was to evaluate the effect of ${\alpha}-lipoic$ acid, a potent free radical scavenger, on the expression of active form of extracellular signal-regulated kinase (pERK1/2) proteins from hindlimb muscles of rats following ischemia-reperfusion injury. Material and methods: 64 health, $280{\sim}350\;g$ weighted Sprague-Dawley male rats were used. In order to make a muscle flap, the gastrocnemius (GC) and soleus (SOL) muscles were dissected and elevated. The popliteal artery was occluded for 4hours and reperfused for 10 minutes, 30 minutes, 1 hour, 2 hours and 4 hours, respectively. Results: The ischemia by occlusion of the popliteal artery itself caused a minimal change in expression of phosphorylated form of proteins observed in hindlimb muscle. In contrast, after 4 hours of ischemia, immunoreactivity for pERK1/2 in the GC muscle showed dual peaks at 10 minutes and 4 hours after reperfusion. In ${\alpha}-lipoic$ acid treated group, the expression of pERK1/2 was increased significantly compared to I/R-only group. Conclusion: These results suggest that ${\alpha}-lipoic$ acid may protect I/R injury of the skeletal muscle through free radical scavening and activation of intracellular pERK1/2 expression.

• Korean Circulation Journal
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• 제53권6호
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• pp.387-403
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• 2023

Background and Objectives: Myocardial ischemia and reperfusion injury (MIRI) has high morbidity and mortality worldwide. We aimed to explore the role of long noncoding RNA lysyl oxidase like 1 antisense RNA 1 (LOXL1-AS1) in cardiomyocyte pyroptosis. Methods: Hypoxia/reoxygenation (H/R) injury was constructed in human cardiomyocyte (HCM). The level of LOXL1-AS1, miR-761, phosphatase and tensin homolog (PTEN) and pyroptosis-related proteins was monitored by quantitative real-time polymerase chain reaction or western blot. Flow cytometry examined the pyroptosis level. Lactate dehydrogenase (LDH), creatine kinase-MB and cardiac troponin I levels were detected by test kits. Enzyme-linked immunosorbent assay measured the release of inflammatory cytokines. Dual-luciferase assay validated the binding relationship among LOXL1-AS1, miR-761, and PTEN. Finally, ischemia/reperfusion (I/R) animal model was constructed. Hematoxylin and eosin staining assessed morphological changes of myocardial tissue. NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and casepase-1 expression was determined by immunohistochemistry. Results: After H/R treatment, LOXL1-AS1 and PTEN were highly expressed but miR-761 level was suppressed. LOXL1-AS1 inhibition or miR-761 overexpression increased cell viability, blocked the release of LDH and inflammatory cytokines (interleukin [IL]-1β, IL-18), inhibited pyroptosis level, and downregulated pyroptosis-related proteins (ASC, cleaved caspase-1, gasdermin D-N, NLRP3, IL-1β, and IL-18) levels in HCMs. LOXL1-AS1 sponged miR-761 to up-regulate PTEN. Knockdown of miR-761 reversed the effect of LOXL1-AS1 down regulation on H/R induced HCM pyroptosis. LOXL1-AS1 aggravated the MIRI by regulating miR-761/PTEN axis in vivo. Conclusions: LOXL1-AS1 targeted miR-761 to regulate PTEN expression, then enhance cardiomyocyte pyroptosis, providing a new alternative target for the treatment of MIRI.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.340-340
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• 1994

Since total hepatic ischemia(IS) occurs with transplantation, there has been interest in evaluating hepatic function after ischemia and subsequent reflow of blood. Four groups of animals were studied: group 1 (sham), group 2 (30mins IS), group 3 (60mins IS), and g.cup 4 (90mins IS). Serum transaminase(STA), wet weight-to-dry weight ratio(W/D), lipid peroxides(LPO), glucose-6-phosphatase(G-6-Pase) activity, Na$\^$+//K$\^$+/-ATPase(ATPase) activity were measured at 1, 5 and 24hrs after hepatic ischemia. Significant changes occurred between 1 and 5hrs of reperfusion. STA was 3579${\pm}$401, 4593${\pm}$675 and 6348${\pm}$808 U/L in group 2, 3 and 4 respectively. These changes were ischemic time-dependent manner. W/D in group 3 and 4 were significantly increased than that in sham group at all time points measured. In sham group, the level of LPO in the liver microsome remained constant at approximately 0. 5nmole MDA formed/mg protein througllout the experiment, In all ischemic groups on the other hand, the level of LPO started to increase at ischemia and markedly increased at all reperfusion period. Similar to STA, these changes were also dependent on duration of ischemia. Although G-6-Pase activity remained unchanged in both group 2 and group 3 until 5hrs of reperfusion, marked decrease in G-6-Pase activity was observed at grcup 4. ATPase activity was significantly decreased at 1, 5 and 24 hrs of reperfusion in group 3, whereas it was not changed in group 2. Furthermore, ATPase activity in group 4 started to decrease at ischemia and markedly decreased for entire reperfusion period. These data suggest that severity of hepatocellular injury is associated with period of ischemia as well as period of reperfusion.

• Biomolecules & Therapeutics
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• 제6권4호
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• pp.358-363
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• 1998

Intravenous lipid emulsion is used extensively as a major component of parenteral nutrition for patients in the surgical intensive care unit. Abnormal cardiovascular function related to lipid infusion has been reported although conflicting results exist. In the present study, we investigated the effects of intravenous emulsions of long-chain triglyceride (LCT) and medium-chain triglyceride (MCT) on myocardial ischemia/ reperfusion injury and on platelet aggregation in rat. There was no difference between LCT and MCT considering the effects on left ventricular developed pressure (LVDP) and coronary flow rate (CFR) before and after ischemia/reperfusion in isolated rat heart. On the other hand, a difference was found between LCT and MCT with regard to their effects on heart rate (HR) and end diastolic pressure (EDP) after ischemia/reperfusion. After ischemia/reperfusion, HR was significantly (P<0.05) reduced and EDP significantly (P<0.05) inc.eased by LCT (18$\pm$2.0% and 42.8$\pm$8.9%, respectively), but not by MCT Ex vivo platelet aggregation induced by collagen was reduced by LCT infusion, but not by MCT These findings suggest that MCT may have slightly more favorable effect than LCT on the myocardial function after ischemia/reperfusion in rat.

• 생명과학회지
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• 제19권5호
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• pp.644-651
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• 2009

The objective of this study was to identify EXE (1 hr a day at 21 m/min for 5 day/wk, at 0 % grade for 6 wk) on myocardium glucose metabolic phenotypic proteins (AMPK-PGC-1${\alpha}$-GLUT-4) and HSP-60 protein expression after ischemia/reperfusion injury (IRI) in STZ-induced rats. EXE was performed using STZ-induced diabetic rats on a rodent treadmill (28 m/min, 1 hr/day, 5 day/wk for 6 wk). The results of this study suggest that i) serum insulin level was not changed among groups (p>l0.05). ii) the LVDP level increased significantly in the STZ-EXE-IRI group compared to the STZ-IRI group at 60 min (p<0.01), 70 min (p<0.05) and 80 min (p<0.05) after reperfusion, respectively, and iii) AMPK phosphorylation (p<0.01), PGC-1${\alpha}$ protein (p<0.001), GLUT-4 protein (p<0.001) and HSP-60 protein expressions (p<0.05) increased significantly in the STZ-EXE-IRI group compared to the STZ-IRI group. In conclusion, the findings of the present study reveal that EXE may provide therapeutic value to insulin dependent diabetic patients with peripheral insulin resistance and myocardium injury by improving glucose metabolic proteins (AMPK-PGC-1${\alpha}$-GLUT-4) and heat shock protein-60 (HSP-60), along with increasing LVDP levels and decreasing glucose levels. Therefore, EXE protects the STZ-induced diabetic myocardium injury against ischemia/ reperfusion injury.