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.

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.

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.

Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: Beyond ischemia-reperfusion injury

Common gastrointestinal diseases such as radiation enteritis(RE),acute pancreatitis,inflammatory bowel diseases(IBD)and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level,mostly involving the activation of many pathways of the immune response,ultimately leading to tissue injury.Increased oxidative stress,inflammatory cytokine release,inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities.Treatment varies in each specific disease,but at least in the cases of RE and IBD immunosuppressors are effective.However,full therapeutic responses are not always achieved.The pathophysiology of ischemiareperfusion(IR)injury shares many of these mechanisms.Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs,a phenomenon called remote ischemic preconditioning(RIP).This procedure has been shown to protect the gut,pancreas and liver by modulating many of the same inflammatory mechanisms.Since RIP is safe and tolerable,and has shown to be effective in some recent clinical trials,I suggest that RIP could be used as a physiologicallyrelevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions.

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.

Impact of remote ischemic preconditioning on wound healing in small bowel anastomoses

AIM： To investigate the influence of remote ischemic preconditioning （RIPC） on anastomotic integrity. METHODS： Sixty male Wistar rats were randomized to six groups. The control group （n = 10） had an end- to-end ileal anastomosis without RIPC. The preconditioned groups （n = 34） varied in time of ischemia and time of reperfusion. One group received the amino acid L-arginine before constructing the anastomosis （n = 9）. On postoperative day 4, the rats were re-laparotomized, and bursting pressure, hydroxyproline concentration, intra-abdominal adhesions, and a histological score concerning the mucosat ischemic injury were collected. The data are given as median （range）.RESULTS： On postoperative day 4, median bursting pressure was 124 mmHg （60-146 mmHg） in the control group. The experimental groups did not show a statistically significant difference （P 〉 0.05）. Regarding the hydroxyproline concentration, we did not find any significant variation in the experimental groups. We detected significantly less mucosal injury in the RIPC groups. Furthermore, we assessed more extensive intra-abdominal adhesions in the preconditioned groups than in the control group. CONCLUSION： RIPC directly before performing small bowel anastomosis does not affect anastomotic stability in the early period, as seen in ischemic preconditioning.

Randomized controlled trial of remote ischemic preconditioning and atrial fibrillation in patients undergoing cardiac surgery

AIM To study whether remote ischemic preconditioning(RIPC) has an impact on clinical outcomes, such as post-operative atrial fibrillation(POAF).METHODS This was a prospective, single-center, single-blinded,randomized controlled study. One hundred and two patients were randomized to receive RIPC(3 cycles of 5 min ischemia and 5 min reperfusion in the upper arm after induction of anesthesia) or no RIPC(control). Primary outcome was POAF lasting for five minutes or longer during the first seven days after surgery. Secondary outcomes included length of hospital stay, incidence of inpatient mortality, myocardial infarction, and stroke. RESULTS POAF occurred at a rate of 54% in the RIPC group and 41.2% in the control group(P = 0.23). No statistically significant differences were noted in secondary outcomes between the two groups. CONCLUSION This is the first study in the United States to suggest that RIPC does not reduce POAF in patients with elective or urgent cardiac surgery. There were no differences in adverse effects in either group. Further studies are required to assess the relationship between RIPC and POAF.

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.