AIM:To characterize the impact of the Pringle ma-neuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who un-derwent hepatic...AIM:To characterize the impact of the Pringle ma-neuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who un-derwent hepatic resection under in flow occlusion were randomized either to receive PM alone (n = 31) or IP (10 min of ischemia followed by 10 min of reperfusion) prior to PM (n = 30). Quantification of liver perfusion was measured by Doppler probes at the hepatic artery and portal vein at various time points after reperfusion of remnant livers. RESULTS: Occlusion times of 33 ± 12 min (mean ± SD) and 34 ± 14 min and the extent of resected liver tissue (2.7 segments) were similar in both groups. In controls (PM), on reperfusion of liver remnants for 15 min, portal perfusion markedly decreased by 29% while there was a slight increase of 8% in the arterial blood flow. In contrast, following IP + PM the portal vein flow remained unchanged during reperfusion and a significantly increased arterial blood flow (+56% vs baseline) was observed. In accordance with a better postischemic blood supply of the liver, hepatocellular injury, as measured by alanine aminotransferase (ALT) levels on day 1 was considerably lower in group B compared to group A (247 ± 210 U/I vs 550 ± 650 U/I, P < 0.05). Additionally, ALT levels were significantly correlated to the hepatic artery in flow.CONCLUSION: IP prevents postischemic flow reduction of the portal vein and simultaneously increases arterial perfusion, suggesting that improved hepatic macrocirculation is a protective mechanism following hepatectomy.展开更多
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 e...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.展开更多
AIM: To explore if ischemic preconditioning(IPC) can enhance the survival of retinal ganglion cells(RGCs) after optic nerve axotomy. METHODS: Twenty-four hours prior to retinal ischemia 60 min or axotomy, IPC was appl...AIM: To explore if ischemic preconditioning(IPC) can enhance the survival of retinal ganglion cells(RGCs) after optic nerve axotomy. METHODS: Twenty-four hours prior to retinal ischemia 60 min or axotomy, IPC was applied for ten minutes in groups of(n=72) animals. The survival of RGCs, the cellular expression of heat shock protein 27(HSP27) and heat shock protein 70(HSP70) and the numbers of retinal microglia in the different groups were quantified at 7 and 14 d post-injury. The cellular expression of HSP27 and HSP70 and changes in the numbers of retinal microglia were quantified to detect the possible mechanism of the protection of the IPC. RESULTS: Ten minutes of IPC promoted RGC survival in both the optic nerve injury(IPC-ONT) and the retinal ischemia 60min(IPC-IR60) groups, examined at 7d and 14 d post-injury. Microglial proliferation showed little correlation with the extent of benefit effects of IPC on the rescue of RGCs. The number of HSP27-positive RGCs was significantly higher in the IPC-ONT group than in the sham IPC-ONT group, although the percentage of HSP27-positive RGCs did not significantly differ between groups. For the IPC-IR60 group, neither the number nor the percentage of the HSP27-positive RGCs differed significantly between the IPC and the sham-operated groups. The number of HSP70-positive RGCs was significantly higher for both the IPC-ONT and the IPC-IR60 experimental groups, but the percentages did not differ. CONCLUSION: The induction of IPC enhances the survival of RGCs against both axotomy and retinal ischemia.展开更多
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 ...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.展开更多
Liver ischemia-reperfusion injury is a major cause of postoperative liver dysfunction,morbidity and mortality following liver resection and transplantation.Ischemic conditioning has been shown to ameliorate ischemiare...Liver ischemia-reperfusion injury is a major cause of postoperative liver dysfunction,morbidity and mortality following liver resection and transplantation.Ischemic conditioning has been shown to ameliorate ischemiareperfusion injury in small animal models.It can be applied directly or remotely when cycles of ischemia and reperfusion are applied to a distant site or organ.Considering timing of the procedure,different protocols are available.Ischemic preconditioning refers to that performed before the duration of ischemia of the target organ.Ischemic perconditioning is performed over the duration of ischemia of the target organ.Ischemic postconditioning applies brief episodes of ischemia at the onset of reperfusion following a prolonged ischemia.Animal studies pointed towards suppressing cytokine release,enhancing the production of hepatoprotective adenosine and reducing liver apoptotic response as the potential mechanisms responsible for the protective effect of direct tissue conditioning.Interactions between neural,humoral and systemic pathways all lead to the protective effect of remote ischemic preconditioning.Despite promising animal studies,none of the aforementioned protocols proved to be clinically effective in liver surgery with the exception of morbidity reduction in cirrhotic patients undergoing liver resection.Further human clinical trials with application of novel conditioning protocols and combination of methods are warranted before implementation of ischemic conditioning in day-to-day clinical practice.展开更多
Myocardial infarction is a major cause of death and disability worldwide and myocardial infarct size is a major determinant of prognosis. Early and successful restoration of myocardial reperfusion following an ischemi...Myocardial infarction is a major cause of death and disability worldwide and myocardial infarct size is a major determinant of prognosis. Early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome,but reperfusion may induce further myocardial damage itself. Development of adjunctive therapies to limit myocardial reperfusion injury beyond opening of the coronary artery gains increasing attention. A vast number of experimental studies have shown cardioprotective effects of ischemic and pharmacological conditioning,but despite decades of research,the translation into clinical effects has been challenging. Recently published clinical studies,however,prompt optimism as novel techniques allow for improved clinical applicability. Cyclosporine A,the GLP-1 analogue exenatide and rapid cooling by endovascular infusion of cold saline all reduce infarct size and may confer clinical benefit for patients admitted with acute myocardial infarcts. Equally promising,three follow-up studies of the effect of remote ischemic conditioning(RIC) show clinical prognostic benefit in patients undergoing coronary surgery and percutaneous coronary intervention. The discovery that RIC canbe performed noninvasively using a blood pressure cuff on the upper arm to induce brief episodes of limb ischemia and reperfusion has facilitated the translation of RIC into the clinical arena. This review focus on novel advances in adjunctive therapies in relation to acute and elective coronary procedures.展开更多
Ischemic preconditioning(IPC)is a potential intervention known to protect the heart against ischemia/reperfusion injury,but its role in the no-reflow phenomenon that follows reperfusion is unclear.Dihydrotanshinone I(...Ischemic preconditioning(IPC)is a potential intervention known to protect the heart against ischemia/reperfusion injury,but its role in the no-reflow phenomenon that follows reperfusion is unclear.Dihydrotanshinone I(DT)is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC.Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation(OGD),but the protection was prevented by a ROS scavenger.In addition,DT administration protected the heart against isoprenaline challenge.Mechanistically,PKM2 reacted to transient ROS via oxidization at Cys423/Cys424,leading to glutathionylation and nuclear translocation in dimer form.In the nucleus,PKM2 served as a co-factor to promote HIF-1a-dependent gene induction,contributing to adaptive responses.In mice subjected to permanent coronary ligation,cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection,which was rescued by overexpression of wild-type Pkm2,rather than Cys423/424-mutated Pkm2.In conclusion,PKM2 is sensitive to oxidation,and subsequent glutathionylation promotes its nuclear translocation.Although IPC has been viewed as a protective means against reperfusion injury,our study reveals its potential role in protection of the heart from no-reflow ischemia.展开更多
BACKGROUND Ischemia-reperfusion injury(IRI) is a major risk associated with liver surgery and transplantation,and its pathological mechanism is complex.Interleukin-1 receptor antagonist(IL-1ra) can protect the liver f...BACKGROUND Ischemia-reperfusion injury(IRI) is a major risk associated with liver surgery and transplantation,and its pathological mechanism is complex.Interleukin-1 receptor antagonist(IL-1ra) can protect the liver from IRI.However,the regulatory mechanism of IL-1ra expression is still unclear.AIM To identify the mechanism that could protect the liver in the early stage of IRI.METHODS To screen the key genes in hepatic IRI,we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI.Subsequently,we verified the expression and effect of IL-1ra in hepatic IRI.We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor(HIF)-1α.Finally,to explore the protective mechanism of ischemic preconditioning(IP),we examined the expression of HIF-1α and IL-1ra after IP.RESULTS We identified IL-1ra as a key regulator in hepatic IRI.The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro.Furthermore,we found that HIF-1αregulated Il-1ra transcription in response to hypoxia.Increased HIF-1α accumulation promoted IL-1ra expression,whereas inhibition of HIF-1α exhibited the opposite effect.We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1αactivation.Of note,we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression,which is mediated through HIF-1α.CONCLUSION We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α.Importantly,IP protects the liver from IRI via the HIF-1α–IL-1ra pathway.展开更多
基金Supported by The Deutsche Forschungsgemeinschaft, No. DFG SCHA 857/1-1
文摘AIM:To characterize the impact of the Pringle ma-neuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who un-derwent hepatic resection under in flow occlusion were randomized either to receive PM alone (n = 31) or IP (10 min of ischemia followed by 10 min of reperfusion) prior to PM (n = 30). Quantification of liver perfusion was measured by Doppler probes at the hepatic artery and portal vein at various time points after reperfusion of remnant livers. RESULTS: Occlusion times of 33 ± 12 min (mean ± SD) and 34 ± 14 min and the extent of resected liver tissue (2.7 segments) were similar in both groups. In controls (PM), on reperfusion of liver remnants for 15 min, portal perfusion markedly decreased by 29% while there was a slight increase of 8% in the arterial blood flow. In contrast, following IP + PM the portal vein flow remained unchanged during reperfusion and a significantly increased arterial blood flow (+56% vs baseline) was observed. In accordance with a better postischemic blood supply of the liver, hepatocellular injury, as measured by alanine aminotransferase (ALT) levels on day 1 was considerably lower in group B compared to group A (247 ± 210 U/I vs 550 ± 650 U/I, P < 0.05). Additionally, ALT levels were significantly correlated to the hepatic artery in flow.CONCLUSION: IP prevents postischemic flow reduction of the portal vein and simultaneously increases arterial perfusion, suggesting that improved hepatic macrocirculation is a protective mechanism following hepatectomy.
基金Supported by Renji Hospital Clinical Innovation Foundation,No.PYIII-17-002Outstanding Academic Leaders’Program of Health and Family Planning Commission of Shanghai,No.2017BR042+1 种基金Investigative Doctor Program(2017)of Shanghai Jiao Tong University School of MedicineJoint Project of Health and Family Planning Commission of Pudong District,No.PW2015D-3.
文摘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.
文摘AIM: To explore if ischemic preconditioning(IPC) can enhance the survival of retinal ganglion cells(RGCs) after optic nerve axotomy. METHODS: Twenty-four hours prior to retinal ischemia 60 min or axotomy, IPC was applied for ten minutes in groups of(n=72) animals. The survival of RGCs, the cellular expression of heat shock protein 27(HSP27) and heat shock protein 70(HSP70) and the numbers of retinal microglia in the different groups were quantified at 7 and 14 d post-injury. The cellular expression of HSP27 and HSP70 and changes in the numbers of retinal microglia were quantified to detect the possible mechanism of the protection of the IPC. RESULTS: Ten minutes of IPC promoted RGC survival in both the optic nerve injury(IPC-ONT) and the retinal ischemia 60min(IPC-IR60) groups, examined at 7d and 14 d post-injury. Microglial proliferation showed little correlation with the extent of benefit effects of IPC on the rescue of RGCs. The number of HSP27-positive RGCs was significantly higher in the IPC-ONT group than in the sham IPC-ONT group, although the percentage of HSP27-positive RGCs did not significantly differ between groups. For the IPC-IR60 group, neither the number nor the percentage of the HSP27-positive RGCs differed significantly between the IPC and the sham-operated groups. The number of HSP70-positive RGCs was significantly higher for both the IPC-ONT and the IPC-IR60 experimental groups, but the percentages did not differ. CONCLUSION: The induction of IPC enhances the survival of RGCs against both axotomy and retinal ischemia.
文摘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.
基金Supported by National Science Centre,Poland,No.2019/34/E/NZ5/00433.
文摘Liver ischemia-reperfusion injury is a major cause of postoperative liver dysfunction,morbidity and mortality following liver resection and transplantation.Ischemic conditioning has been shown to ameliorate ischemiareperfusion injury in small animal models.It can be applied directly or remotely when cycles of ischemia and reperfusion are applied to a distant site or organ.Considering timing of the procedure,different protocols are available.Ischemic preconditioning refers to that performed before the duration of ischemia of the target organ.Ischemic perconditioning is performed over the duration of ischemia of the target organ.Ischemic postconditioning applies brief episodes of ischemia at the onset of reperfusion following a prolonged ischemia.Animal studies pointed towards suppressing cytokine release,enhancing the production of hepatoprotective adenosine and reducing liver apoptotic response as the potential mechanisms responsible for the protective effect of direct tissue conditioning.Interactions between neural,humoral and systemic pathways all lead to the protective effect of remote ischemic preconditioning.Despite promising animal studies,none of the aforementioned protocols proved to be clinically effective in liver surgery with the exception of morbidity reduction in cirrhotic patients undergoing liver resection.Further human clinical trials with application of novel conditioning protocols and combination of methods are warranted before implementation of ischemic conditioning in day-to-day clinical practice.
文摘Myocardial infarction is a major cause of death and disability worldwide and myocardial infarct size is a major determinant of prognosis. Early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome,but reperfusion may induce further myocardial damage itself. Development of adjunctive therapies to limit myocardial reperfusion injury beyond opening of the coronary artery gains increasing attention. A vast number of experimental studies have shown cardioprotective effects of ischemic and pharmacological conditioning,but despite decades of research,the translation into clinical effects has been challenging. Recently published clinical studies,however,prompt optimism as novel techniques allow for improved clinical applicability. Cyclosporine A,the GLP-1 analogue exenatide and rapid cooling by endovascular infusion of cold saline all reduce infarct size and may confer clinical benefit for patients admitted with acute myocardial infarcts. Equally promising,three follow-up studies of the effect of remote ischemic conditioning(RIC) show clinical prognostic benefit in patients undergoing coronary surgery and percutaneous coronary intervention. The discovery that RIC canbe performed noninvasively using a blood pressure cuff on the upper arm to induce brief episodes of limb ischemia and reperfusion has facilitated the translation of RIC into the clinical arena. This review focus on novel advances in adjunctive therapies in relation to acute and elective coronary procedures.
基金supported by the National Key R&D Program of China(2019YFC1711000)the National Natural Science Foundation of China(No.81421005)the“111”Project(B16046)from the Ministry of Education of China and the State Administration of Foreign Experts Affairs of China。
文摘Ischemic preconditioning(IPC)is a potential intervention known to protect the heart against ischemia/reperfusion injury,but its role in the no-reflow phenomenon that follows reperfusion is unclear.Dihydrotanshinone I(DT)is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC.Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation(OGD),but the protection was prevented by a ROS scavenger.In addition,DT administration protected the heart against isoprenaline challenge.Mechanistically,PKM2 reacted to transient ROS via oxidization at Cys423/Cys424,leading to glutathionylation and nuclear translocation in dimer form.In the nucleus,PKM2 served as a co-factor to promote HIF-1a-dependent gene induction,contributing to adaptive responses.In mice subjected to permanent coronary ligation,cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection,which was rescued by overexpression of wild-type Pkm2,rather than Cys423/424-mutated Pkm2.In conclusion,PKM2 is sensitive to oxidation,and subsequent glutathionylation promotes its nuclear translocation.Although IPC has been viewed as a protective means against reperfusion injury,our study reveals its potential role in protection of the heart from no-reflow ischemia.
基金the National Natural Science Foundation of China,No.81670600.
文摘BACKGROUND Ischemia-reperfusion injury(IRI) is a major risk associated with liver surgery and transplantation,and its pathological mechanism is complex.Interleukin-1 receptor antagonist(IL-1ra) can protect the liver from IRI.However,the regulatory mechanism of IL-1ra expression is still unclear.AIM To identify the mechanism that could protect the liver in the early stage of IRI.METHODS To screen the key genes in hepatic IRI,we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI.Subsequently,we verified the expression and effect of IL-1ra in hepatic IRI.We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor(HIF)-1α.Finally,to explore the protective mechanism of ischemic preconditioning(IP),we examined the expression of HIF-1α and IL-1ra after IP.RESULTS We identified IL-1ra as a key regulator in hepatic IRI.The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro.Furthermore,we found that HIF-1αregulated Il-1ra transcription in response to hypoxia.Increased HIF-1α accumulation promoted IL-1ra expression,whereas inhibition of HIF-1α exhibited the opposite effect.We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1αactivation.Of note,we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression,which is mediated through HIF-1α.CONCLUSION We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α.Importantly,IP protects the liver from IRI via the HIF-1α–IL-1ra pathway.
