Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion

AIM:To study the effects of preconditioning on inducible nitric oxide synthase(iNOS)and interleukin 1(IL-1)receptor transcription in rat liver ischemia/reperfusion injury(IRI).METHODS:Seventy-two male rats were randomized into 3 groups:the one-hour segmental ischemia(IRI,n=24)group,the ischemic preconditioning(IPC,n=24)group or the remote ischemic preconditioning(RIPC,n=24)group.The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion.The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR.The total Nitrite and Nitrate(NOx)in continuously sampled microdialysate(MD)from the liver was analyzed.In addition,the NOx levels in the serum were analyzed.RESULTS:After 4 h of reperfusion,the iNOS mRNA was significantly higher in the R-IPC(ΔCt:3.44±0.57)group than in the IPC(ΔCt:5.86±0.82)group(P=0.025).The IL-1 receptor transcription activity was reduced in the IPC group(ΔCt:1.88±0.53 to 4.81±0.21),but not in the R-IPC group,during reperfusion(P=0.027).In the MD,a significant drop in the NOx levels was noted in the R-IPC group(12.3±2.2 to 4.7±1.2μmol/L)at the end of ischemia compared with the levels in early ischemia(P=0.008).A similar trend was observed in the IPC group(11.8±2.1 to 6.4±1.5μmol/L),although this difference was not statistically significant.The levels of NOx rose quickly during reperfusion in both groups.CONCLUSION:IPC,but not R-IPC,reduces iNOS and IL-1 receptor transcription during early reperfusion,indicating a lower inflammatory reaction.NOx is consumed in the ischemic liver lobe.

Remote ischemic preconditioning protects liver ischemia-reperfusion injury by regulating eNOS-NO pathway and liver microRNA expressions in fatty liver rats

BACKGROUND: Ischemic preconditioning (IPC) is a strategy to reduce ischemia-reperfusion (I/R) injury. The protective effect of remote ischemic preconditioning (RIPC) on liver I/R injury is not clear. This study aimed to investigate the roles of RIPC in liver I/R in fatty liver rats and the involvement of endothelial nitric oxide synthase-nitric oxide (eNOS-NO) pathway and microRNA expressions in this process. METHODS: A total of 32 fatty rats were randomly divided into the sham group, I/R group, RIPC group and RIPC+I/R group. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and nitric oxide (NO) were measured. Hematoxylin-eosin staining was used to observe histological changes of liver tissues, TUNEL to detect hepatocyte apoptosis, and immunohistochemistry assay to detect heat shock protein 70 (HSP70) expression. Western blotting was used to detect liver inducible NOS (iNOS) and eNOS protein levels and realtime quantitative polymerase chain reaction to detect miR-34a, miR-122 and miR-27b expressions. RESULTS: Compared with the sham and RIPC groups, serum ALT, AST and iNOS in liver tissue were significantly higher in other two groups, while serum NO and eNOS in liver tissue were lower, and varying degrees of edema, degeneration and inflammatory cell infiltration were found. Cell apoptosis number was slightly lower in the RIPC+I/R group than that in I/R group. Compared with the sham group, HSP70 expressions were significantly increased in other three groups (all P<0.05). Compared with the sham and RIPC groups, elevated miR-34a expressions were found in I/R and RIPC+I/R groups (P<0.05). MiR-122 and miR-27b were found significantly decreased in I/R and RIPC+I/R groups compared with the sham and RIPC groups (all P<0.05). CONCLUSION: RIPC can reduce fatty liver I/R injury by affecting the eNOS-NO pathway and liver microRNA expressions.

Protective effects of remote ischemic preconditioning in rat hindlimb on ischemia- reperfusion injury

Three cycles of remote ischemic pre-conditioning induced by temporarily occluding the bilateral femoral arteries （10 minutes） prior to 10 minutes of reperfusion were given once a day for 3 days before the animal received middle artery occlusion and reperfusion surgery. The results showed that brain infarct volume was significantly reduced after remote ischemic pre-conditioning. Scores in the forelimb placing test and the postural reflex test were significantly lower in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. Thus, neurological function was better in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. These results indicate that remote ischemic pre-conditioning in rat hindlimb exerts protective effects in ischemia-reperfusion injury.

Effect of remote ischemic preconditioning among donors and recipients following pediatric liver transplantation:A randomized clinical trial

BACKGROUND Studies suggested that remote ischemic preconditioning(RIPC)may effectively lessen the harmful effects of ischemia reperfusion injury during organ transplantation surgery.AIM To investigate the protective effects of RIPC on living liver donors and recipients following pediatric liver transplantation.METHODS From January 2016 to January 2019 at Renji Hospital Affiliated with Shanghai Jiao Tong University School of Medicine,208 donors were recruited and randomly assigned to four groups:S-RIPC group(no intervention;n=55),D-RIPC group(donors received RIPC;n=51),R-RIPC group(recipients received RIPC,n=51)and DR-RIPC group(both donors and recipients received RIPC;n=51).We primarily evaluated postoperative liver function among donors and recipients and incidences of early allograft dysfunction,primary nonfunction and postoperative complications among recipients.RESULTS RIPC did not significantly improve alanine transaminase and aspartate aminotransferase levels among donors and recipients or decrease the incidences of early allograft dysfunction,primary nonfunction,and postoperative complications among recipients.Limited protective effects were observed,including a lower creatinine level in the D-RIPC group than in the S-RIPC group on postoperative day 0(P<0.05).However,no significant improvements were found in donors who received RIPC.Furthermore,RIPC had no effects on the overall survival of recipients.CONCLUSION The protective effects of RIPC were limited for recipients who received living liver transplantation,and no significant improvement of the prognosis was observed in recipients.

Downregulation of Na^＋/Ca^2＋ Exchanger Isoform 1 Protects Isolated Hearts by Sevoflurane Postconditioning but Not by Delayed Remote Ischemic Preconditioning in Rats

Background：Calcium regulatory proteins-L-type Ca^2＋ channels （LTCCs）,ryanodine receptor 2 （RyR2）,and Na^＋/Ca^2＋ exchanger isoform 1 （NCX1） have been recognized as important protective mechanisms during myocardial ischemia-reperfusion injury （I/RI）.Both sevofturane postconditioning （SevoPoC） and delayed remote ischemic preconditioning （DRIPC） have been shown to protect the heart against I/RI.In this study,we aimed to compare the effects of SevoPoC and DRIPC on the expression of the three calcium regulatory proteins in an isolated rat heart model.Methods：After 30-min balanced perfusion,isolated hearts from rats were subjected to 30-min ischemia followed by 60-min reperfusion.Totally 40 isolated hearts were randomly assigned to four groups （n =10/group）：time control group,I/RI group,SevoPoC group,and DRIPC group.The effect of SevoPoC （3% v/v） and DRIPC were observed.Myocardial infarct size （IS）,cardiac troponin I level,and heart function were measured.The protein and messenger RNA levels of LTCCs,RyR2,and NCX1 were determined.Results：Both SevoPoC and DRIPC improved the recovery of myocardial function,and reduced cardiac troponin Ⅰ release after I/RI.The decrease in IS was more significant in the SevoPoC group than that in the DRIPC group （16.50% ± 4.54% in the SevoPoC group [P =0.0006],and 22.34% ± 4.02% in the DRIPC group [P =0.0007] vs.35.00% ± 5.24% in the I/RI group,respectively）.SevoPoC,but not DRIPC significantly inhibited the activity of NCX 1 （0.59 ＋ 0.09 in the I/RI group vs.0.32 ± 0.16 in the SevoPoC group,P =0.006;vs.0.57 ± 0.14 in the DRIPC group,P =0.072）.No statistical significant differences were observed in the expression of LTCCs and RyR2 between SevoPoC and DRIPC.In addition,subsequent correlation analysis showed a significantly positive relationship between the cardiac troponin Ⅰ level and the protein expression ofNCX1 （r =0.505,P =0.023）.Conclusion：SevoPoC may be more effective in the cardioprotection than DRIPC partly due to the deactivation of NCX1.

Remote ischemia conditioning-an endogenous cardioprotective strategy from outside the heart

Objective A general review was made of studies involving： （1） The experimental evidence of remote ischemic preconditioning （RIPC） and relative clinical studies, （2） The experimental and clinical evidences of remote ischemic postconditioning （RIPOC）, （3） The potential mechanistic pathways underlying their protective effects.Data sources The data used in this review were mainly from manuscripts listed in PubMed that were published in English from 1986 to 2010. The search terms were ＂myocardial ischemia reperfusion injury＂, ＂ischemia preconditioning＂,＂ischemia postconditioning＂, ＂remote preconditioning＂ and ＂remote postconditioning＂.Study selection （1） Clinical and experimental evidence that both RIPC and RIPOC produce preservation of ischemia reperfusion injury （IRI） of myocardium and other organs, （2） Studies related to the potential mechanisms, by which remote ischemic conditioning protects myocardium against IRI.Results Both RIPC and RIOPC have been shown to attenuate myocardial IRI in laboratory animals. Also, their cardioprotective effects have appeared in some clinical studies. Except the external, the detailed internal mechanisms of remote ischemic conditioning have been generally described. Through these descriptions better protocols can be developed to provide improved cardioprotective procedures.Conclusions Remote ischemic conditioning is an endogenous cardioprotective mechanism from outside the heart that protects against myocardial IRI and represents a general form of inter-organ protection. Remote ischemic conditioning may have an immense impact on clinical practice in the near future.

远程预缺血的心肌保护机制

Remote myocardial preconditioning can protect myocardium. Some bioactive substances released from noncardiac tissues which suffer from ischemia and reperfusion protects the heart by neuronal and humoral paths. Preconditioning at a distance can attenuate myocardial intracellular acidosis and Ca2+ overload,reduce neutrophil and platelet infiltration, protect mitochondrial function and reduce free radicals. This method is simple to apply and have some clinical value. In order to safely apply this method to clinic, a further study on the remote myocardial preconditioning and its mechanism is necessary.