自由基、高压氧与心肌缺血适应
转载请注明来自丁香园
在在1993年有人就进行了一个实验证明，高压氧可通过自由基提高心肌的适应缺血能力，最近，有一系列报道关于该方法的应用，由于高压氧使用方便，可控制，操作性强，比其他适应方法，如缺血，细胞因子、药物等有更明显的优势，现在心外科手术非常普遍，使用高压氧作为一种预防损伤的方法，将对临床有很大意义。
1993年L. Sterling的开创性工作。
http://gateway.ut.ovid.com/gw1/ovidweb.cgi?T=JS&PAGE=fulltext&D=ovft&AN=00003017-199310000-00058&NEWS=N&CSC=Y&CHANNEL=PubMed
L. Sterling, Diana BS; D. Thornton, Jon PhD; Swafford, AMbert BS; Gottlieb, Sheldon F. PhD; Bishop, Sanford P. DVM, PhD; Stanley, Alfred W.H. MD; Downey, James M. PhD
Institution Department of Biological Sciences (D.L.S., S.F.G.) and the Department of Medical Physiology (J.T., A.S., J.M.D.), University of South Alabama, Mobile; Jo Ellen Smith Memorial Baromedical Research Institute (S.F.G.), New Orleans; the Department of Pathology (S.P.B.), University of Alabama at Birmingham; and Kemp-Carraway Heart Institute (A.W.H.S.), Birmingham, Ala.
Title Hyperbaric Oxygen Limits Infarct Size in Ischemic Rabbit Myocardium In Vivo.[Article]
Source Circulation. 88(4) (Part 1):1931-1936, October 1993.
Abstract Background: We explored the ability of increased oxygen pressure to modify necrosis in an open-chest rabbit model of myocardial ischemia and reperfusion.
Methods and Results: A branch of the left coronary artery was occluded for 30 minutes followed by 3 hours of reperfusion. Infarction was measured by triphenyl tetrazolium staining and expressed as a percentage of the ischemic zone. Untreated rabbits were ventilated with 100% oxygen at 1 atm absolute. Treatment animals were exposed to hyperbaric oxygen at 2.5 atm absolute. The l.O-atm control hearts developed 41.5+/-4.6% infarction of the ischemic zone. Animals exposed to hyperbaric oxygen during ischemia only, reperfhsion only, or ischemia and reperfusion had significantly smaller infarcts with respect to control animals (16.2+/-2.9%, 14.5+/-3.7%,. and 9.8+/-2.7%, respectively; P$.01), indicating that they had been protected by the procedure. When hyperbaric oxygen was begun 30 minutes after the onset of reperfusion, no protection was seen (35.8+/-3.8%).
Concuvions. We conclude that hyperbaric oxygen limits infarct size in the reperfused rabbit heart and that the effect can be achieved when hyperbaric oxygen is begun at reperfusion.
最近的综述性文献：
Hyperbaric oxygen: a new drug in myocardial revascularization and protection?
Jeysen Zivan Yogaratnam,Gerard Laden, Leigh Anthony Madden, Ann-Marie Seymour,Levant Guvendika, Mike Cowena, John Greenmanc, Alex Calea, Steve Griffina
Received 5 February 2006; accepted 17 April 2006
Abstract Ischemia–reperfusion injury (IRI) occurs following coronary artery revascularization. Reactive oxygen species (ROS) were initially thought to play a role in the pathogenesis of this injury. However, the evidence for this is inconclusive. Recent studies involving ischemic preconditioning have identified ROS as potential mediators for the cardioprotective effects observed following this technique. Furthermore, cardiac studies involving IRI and the use of hyperbaric oxygen (HBO) have
demonstrated the ability of HBO to induce cardioprotection and to attenuate IRI. This review suggests the possible role for HBO as a new drug in the arena of myocardial revascularization and cellular protection. While there is mounting clinical evidence for this, a methodological understanding of HBO’s cellular mechanisms of actions appears to be lacking. As such, this article attempts to draw the similarity between HBO and other protective oxidative stress mechanisms and then to speculate in an evidence-based manner its possible cellular mechanistic role as a drug via the generation of ROS.
Keywords: Ischemia–reperfusion; Hyperbaric oxygen; Reactive oxygen species; Myocardial protection
心缺血再灌注可以诱导热休克蛋白发挥保护作用，这些蛋白的诱导与自由基有关。
Reperfusion causes significant activation of heat shock transcription factor 1 in ischemic rat heart.
Nishizawa J, Nakai A, Higashi T, Tanabe M, Nomoto S, Matsuda K, Ban T, Nagata K.
BACKGROUND: The myocardial protective role of heat shock protein (HSP) has been demonstrated, and there has been increasing interest in stress response in the heart. We examined the DNA-binding activity of heat shock transcription factor (HSF), by which the transcription of heat shock genes is mainly regulated, during heat shock or ischemia/reperfusion in isolated rat heart. METHODS AND RESULTS: Rat hearts were isolated and perfused with Krebs-Henseleit buffer by the Langendorff method. Whole-cell extracts were prepared for gel mobility shift assay using oligonucleotides containing the heat shock element, which is present upstream of all heat shock genes. Induction of mRNAs for HSP70, HSP90, and GRP78 (glucose-regulated protein) was examined by Northern blot analysis. Although the activation of HSF during global ischemia was weak and rapidly attenuated, postischemic reperfusion induced a significant activation of HSF. In addition, although HSP70 mRNA was hardly induced during ischemia, its burst induction was detected during postischemic reperfusion. Supershift assays using specific antisera for HSF1 and HSF2 revealed that ischemia/reperfusion as well as heat shock induced the activation of HSF1 in hearts. Although the expression of HSP70 mRNA during heat shock was more vigorous than the expression during ischemia/reperfusion, the induction of HSP90 mRNA in postischemic reperfusion was significantly greater than that in heat shock. CONCLUSIONS: Our findings demonstrated that reperfusion causes a significant activation of HSF1 in ischemia-reperfused heart. The striking contrast between the induction of HSP70 mRNA and that of HSP90 mRNA suggests the presence of regulatory mechanisms other than HSF.
使用ROS 清除剂可以消除缺血适应效应
Free Radic Biol Med. 1998 Mar 15;24(5):869-75.
Oxidative stress developed during the reperfusion of ischemic myocardium induces apoptosis.
Maulik N, Yoshida T, Das DK.
Apoptosis or programmed cell death is a genetically controlled response for cells to commit suicide and, is associated with DNA fragmentation or laddering. The common inducers of apoptosis include oxygen free radicals/oxidative stress and Ca2+ which are also implicated in the pathogenesis of myocardial ischemic reperfusion injury. To examine whether ischemic reperfusion injury is mediated by apoptotic cell death, isolated perfused rat hearts were subjected to 15, 30 or 60 min of ischemia as well as 15 min of ischemia followed by 30, 60 or 120 min of reperfusion. At the end of each experiment, hearts were processed for the evaluation of apoptosis, DNA laddering. Apoptosis was studied by visualizing the apoptotic cardiomyocytes by direct fluorescence detection of digoxigenin-labeled genomic DNA using APOPTAG in situ apoptosis detection kit. DNA laddering was evaluated by subjecting the DNA obtained from the hearts to 1.8% agarose gel electrophoresis and photographed under UV illumination. The results of our study revealed apoptotic cells only in the 60 and 120 min reperfused hearts as demonstrated by the intense fluorescence of the immunostained digoxigenin-labeled genomic DNA when observed under fluorescence microscopy. None of the ischemic hearts showed any evidence of apoptosis. These results corroborated with the findings of DNA fragmentation which showed increased ladders of DNA bands in the same reperfused hearts representing integer multiples of the intenucleosomal DNA length (about 180 bp). The presence of apoptotic cells and DNA fragmentation in the myocardium were abolished by preperfusing the hearts in the presence of ebselen, which also removed the oxidative stress developed in the heart. Taken together, these results clearly demonstrate that oxidative stress developed in the ischemic reperfused myocardium induces apoptosis.
ROS具有信号传导作用，science文章
Science. 1996 Nov 15;274(5290):1194-7.
Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors.
Rosette C, Karin M.
Exposure of mammalian cells to ultraviolet (UV) light or high osmolarity strongly activates the c-Jun amino-terminal protein kinase (JNK) cascade, causing induction of many target genes. Exposure to UV light or osmotic shock induced clustering and internalization of cell surface receptors for epidermal growth factor (EGF), tumor necrosis factor (TNF), and interleukin-1 (IL-1). Activation of the EGF and TNF receptors was also detected biochemically. Whereas activation of each receptor alone resulted in modest activation of JNK, coadministration of EGF, IL-1, and TNF resulted in a strong synergistic response equal to that caused by exposure to osmotic shock or UV light. Inhibition of clustering or receptor down-regulation attenuated both the osmotic shock and UV responses. Physical stresses may perturb the cell surface or alter receptor conformation, thereby subverting signaling pathways normally used by growth factors and cytokines.
Hyperbaric Oxygen Treatments Mobilize Stem Cells, University Of Pennsylvania School Of Medicine
Main Category: Stem Cell Research News
Article Date: 29 Dec 2005 - 15:00pm (PST)
According to a study to be published in the American Journal of Physiology-Heart and Circulation Physiology, a typical course of hyperbaric oxygen treatments increases by eight-fold the number of stem cells circulating in a patient's body. Stem cells, also called progenitor cells are crucial to injury repair. The study currently appears on-line and is scheduled for publication in the April 2006 edition of the American Journal.
Stem cells exist in the bone marrow of human beings and animals and are capable of changing their nature to become part of many different organs and tissues. In response to injury, these cells move from the bone marrow to the injured sites, where they differentiate into cells that assist in the healing process. The movement, or mobilization, of stem cells can be triggered by a variety of stimuli - including pharmaceutical agents and hyperbaric oxygen treatments. Where as drugs are associated with a host of side effects, hyperbaric oxygen treatments carry a significantly lower risk of such effects.
"This is the safest way clinically to increase stem cell circulation, far safer than any of the pharmaceutical options," said Stephen Thom, MD, Ph.D., Professor of Emergency Medicine at the University of Pennsylvania School of Medicine and lead author of the study. "This study provides information on the fundamental mechanisms for hyperbaric oxygen and offers a new theoretical therapeutic option for mobilizing stem cells."
"We reproduced the observations from humans in animals in order to identify the mechanism for the hyperbaric oxygen effect," added Thom. "We found that hyperbaric oxygen mobilizes stem/progenitor cells because it increases synthesis of a molecule called nitric oxide in the bone marrow. This synthesis is thought to trigger enzymes that mediate stem/progenitor cell release."
Hopefully, future study of hyperbaric oxygen's role in mobilizing stem cells will provide a wide array of treatments for combating injury and disease.
This article is available on the web at: ajpheart.physiology.org/cgi/reprint/00888.2005
PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
Penn Health System comprises: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.
编辑：西门吹血
1993年L. Sterling的开创性工作。
http://gateway.ut.ovid.com/gw1/ovidweb.cgi?T=JS&PAGE=fulltext&D=ovft&AN=00003017-199310000-00058&NEWS=N&CSC=Y&CHANNEL=PubMed
L. Sterling, Diana BS; D. Thornton, Jon PhD; Swafford, AMbert BS; Gottlieb, Sheldon F. PhD; Bishop, Sanford P. DVM, PhD; Stanley, Alfred W.H. MD; Downey, James M. PhD
Institution Department of Biological Sciences (D.L.S., S.F.G.) and the Department of Medical Physiology (J.T., A.S., J.M.D.), University of South Alabama, Mobile; Jo Ellen Smith Memorial Baromedical Research Institute (S.F.G.), New Orleans; the Department of Pathology (S.P.B.), University of Alabama at Birmingham; and Kemp-Carraway Heart Institute (A.W.H.S.), Birmingham, Ala.
Title Hyperbaric Oxygen Limits Infarct Size in Ischemic Rabbit Myocardium In Vivo.[Article]
Source Circulation. 88(4) (Part 1):1931-1936, October 1993.
Abstract Background: We explored the ability of increased oxygen pressure to modify necrosis in an open-chest rabbit model of myocardial ischemia and reperfusion.
Methods and Results: A branch of the left coronary artery was occluded for 30 minutes followed by 3 hours of reperfusion. Infarction was measured by triphenyl tetrazolium staining and expressed as a percentage of the ischemic zone. Untreated rabbits were ventilated with 100% oxygen at 1 atm absolute. Treatment animals were exposed to hyperbaric oxygen at 2.5 atm absolute. The l.O-atm control hearts developed 41.5+/-4.6% infarction of the ischemic zone. Animals exposed to hyperbaric oxygen during ischemia only, reperfhsion only, or ischemia and reperfusion had significantly smaller infarcts with respect to control animals (16.2+/-2.9%, 14.5+/-3.7%,. and 9.8+/-2.7%, respectively; P$.01), indicating that they had been protected by the procedure. When hyperbaric oxygen was begun 30 minutes after the onset of reperfusion, no protection was seen (35.8+/-3.8%).
Concuvions. We conclude that hyperbaric oxygen limits infarct size in the reperfused rabbit heart and that the effect can be achieved when hyperbaric oxygen is begun at reperfusion.
最近的综述性文献：
Hyperbaric oxygen: a new drug in myocardial revascularization and protection?
Jeysen Zivan Yogaratnam,Gerard Laden, Leigh Anthony Madden, Ann-Marie Seymour,Levant Guvendika, Mike Cowena, John Greenmanc, Alex Calea, Steve Griffina
Received 5 February 2006; accepted 17 April 2006
Abstract Ischemia–reperfusion injury (IRI) occurs following coronary artery revascularization. Reactive oxygen species (ROS) were initially thought to play a role in the pathogenesis of this injury. However, the evidence for this is inconclusive. Recent studies involving ischemic preconditioning have identified ROS as potential mediators for the cardioprotective effects observed following this technique. Furthermore, cardiac studies involving IRI and the use of hyperbaric oxygen (HBO) have
demonstrated the ability of HBO to induce cardioprotection and to attenuate IRI. This review suggests the possible role for HBO as a new drug in the arena of myocardial revascularization and cellular protection. While there is mounting clinical evidence for this, a methodological understanding of HBO’s cellular mechanisms of actions appears to be lacking. As such, this article attempts to draw the similarity between HBO and other protective oxidative stress mechanisms and then to speculate in an evidence-based manner its possible cellular mechanistic role as a drug via the generation of ROS.
Keywords: Ischemia–reperfusion; Hyperbaric oxygen; Reactive oxygen species; Myocardial protection
心缺血再灌注可以诱导热休克蛋白发挥保护作用，这些蛋白的诱导与自由基有关。
Reperfusion causes significant activation of heat shock transcription factor 1 in ischemic rat heart.
Nishizawa J, Nakai A, Higashi T, Tanabe M, Nomoto S, Matsuda K, Ban T, Nagata K.
BACKGROUND: The myocardial protective role of heat shock protein (HSP) has been demonstrated, and there has been increasing interest in stress response in the heart. We examined the DNA-binding activity of heat shock transcription factor (HSF), by which the transcription of heat shock genes is mainly regulated, during heat shock or ischemia/reperfusion in isolated rat heart. METHODS AND RESULTS: Rat hearts were isolated and perfused with Krebs-Henseleit buffer by the Langendorff method. Whole-cell extracts were prepared for gel mobility shift assay using oligonucleotides containing the heat shock element, which is present upstream of all heat shock genes. Induction of mRNAs for HSP70, HSP90, and GRP78 (glucose-regulated protein) was examined by Northern blot analysis. Although the activation of HSF during global ischemia was weak and rapidly attenuated, postischemic reperfusion induced a significant activation of HSF. In addition, although HSP70 mRNA was hardly induced during ischemia, its burst induction was detected during postischemic reperfusion. Supershift assays using specific antisera for HSF1 and HSF2 revealed that ischemia/reperfusion as well as heat shock induced the activation of HSF1 in hearts. Although the expression of HSP70 mRNA during heat shock was more vigorous than the expression during ischemia/reperfusion, the induction of HSP90 mRNA in postischemic reperfusion was significantly greater than that in heat shock. CONCLUSIONS: Our findings demonstrated that reperfusion causes a significant activation of HSF1 in ischemia-reperfused heart. The striking contrast between the induction of HSP70 mRNA and that of HSP90 mRNA suggests the presence of regulatory mechanisms other than HSF.
使用ROS 清除剂可以消除缺血适应效应
Free Radic Biol Med. 1998 Mar 15;24(5):869-75.
Oxidative stress developed during the reperfusion of ischemic myocardium induces apoptosis.
Maulik N, Yoshida T, Das DK.
Apoptosis or programmed cell death is a genetically controlled response for cells to commit suicide and, is associated with DNA fragmentation or laddering. The common inducers of apoptosis include oxygen free radicals/oxidative stress and Ca2+ which are also implicated in the pathogenesis of myocardial ischemic reperfusion injury. To examine whether ischemic reperfusion injury is mediated by apoptotic cell death, isolated perfused rat hearts were subjected to 15, 30 or 60 min of ischemia as well as 15 min of ischemia followed by 30, 60 or 120 min of reperfusion. At the end of each experiment, hearts were processed for the evaluation of apoptosis, DNA laddering. Apoptosis was studied by visualizing the apoptotic cardiomyocytes by direct fluorescence detection of digoxigenin-labeled genomic DNA using APOPTAG in situ apoptosis detection kit. DNA laddering was evaluated by subjecting the DNA obtained from the hearts to 1.8% agarose gel electrophoresis and photographed under UV illumination. The results of our study revealed apoptotic cells only in the 60 and 120 min reperfused hearts as demonstrated by the intense fluorescence of the immunostained digoxigenin-labeled genomic DNA when observed under fluorescence microscopy. None of the ischemic hearts showed any evidence of apoptosis. These results corroborated with the findings of DNA fragmentation which showed increased ladders of DNA bands in the same reperfused hearts representing integer multiples of the intenucleosomal DNA length (about 180 bp). The presence of apoptotic cells and DNA fragmentation in the myocardium were abolished by preperfusing the hearts in the presence of ebselen, which also removed the oxidative stress developed in the heart. Taken together, these results clearly demonstrate that oxidative stress developed in the ischemic reperfused myocardium induces apoptosis.
ROS具有信号传导作用，science文章
Science. 1996 Nov 15;274(5290):1194-7.
Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors.
Rosette C, Karin M.
Exposure of mammalian cells to ultraviolet (UV) light or high osmolarity strongly activates the c-Jun amino-terminal protein kinase (JNK) cascade, causing induction of many target genes. Exposure to UV light or osmotic shock induced clustering and internalization of cell surface receptors for epidermal growth factor (EGF), tumor necrosis factor (TNF), and interleukin-1 (IL-1). Activation of the EGF and TNF receptors was also detected biochemically. Whereas activation of each receptor alone resulted in modest activation of JNK, coadministration of EGF, IL-1, and TNF resulted in a strong synergistic response equal to that caused by exposure to osmotic shock or UV light. Inhibition of clustering or receptor down-regulation attenuated both the osmotic shock and UV responses. Physical stresses may perturb the cell surface or alter receptor conformation, thereby subverting signaling pathways normally used by growth factors and cytokines.
Hyperbaric Oxygen Treatments Mobilize Stem Cells, University Of Pennsylvania School Of Medicine
Main Category: Stem Cell Research News
Article Date: 29 Dec 2005 - 15:00pm (PST)
According to a study to be published in the American Journal of Physiology-Heart and Circulation Physiology, a typical course of hyperbaric oxygen treatments increases by eight-fold the number of stem cells circulating in a patient's body. Stem cells, also called progenitor cells are crucial to injury repair. The study currently appears on-line and is scheduled for publication in the April 2006 edition of the American Journal.
Stem cells exist in the bone marrow of human beings and animals and are capable of changing their nature to become part of many different organs and tissues. In response to injury, these cells move from the bone marrow to the injured sites, where they differentiate into cells that assist in the healing process. The movement, or mobilization, of stem cells can be triggered by a variety of stimuli - including pharmaceutical agents and hyperbaric oxygen treatments. Where as drugs are associated with a host of side effects, hyperbaric oxygen treatments carry a significantly lower risk of such effects.
"This is the safest way clinically to increase stem cell circulation, far safer than any of the pharmaceutical options," said Stephen Thom, MD, Ph.D., Professor of Emergency Medicine at the University of Pennsylvania School of Medicine and lead author of the study. "This study provides information on the fundamental mechanisms for hyperbaric oxygen and offers a new theoretical therapeutic option for mobilizing stem cells."
"We reproduced the observations from humans in animals in order to identify the mechanism for the hyperbaric oxygen effect," added Thom. "We found that hyperbaric oxygen mobilizes stem/progenitor cells because it increases synthesis of a molecule called nitric oxide in the bone marrow. This synthesis is thought to trigger enzymes that mediate stem/progenitor cell release."
Hopefully, future study of hyperbaric oxygen's role in mobilizing stem cells will provide a wide array of treatments for combating injury and disease.
This article is available on the web at: ajpheart.physiology.org/cgi/reprint/00888.2005
PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
Penn Health System comprises: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.
编辑：西门吹血
作者: sunxjk 等
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