Reperfusion injury

Reperfusion injury
Reperfusion injury
Classification and external resources
MeSH D015427

Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.

Contents

Mechanisms of reperfusion injury

The inflammatory response partially mediates the damage of reperfusion injury. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage.[1] The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis. Leukocytes may also bind to the endothelium of small capillaries, obstructing them and leading to more ischemia.[1]

Reperfusion injury plays a part in the brain's ischemic cascade, which is involved in stroke and brain trauma. Similar failure processes are involved in brain failure following reversal of cardiac arrest;[2] control of these processes is the subject of ongoing research. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcers.[3] Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a wound.[3]

In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product of ATP metabolism. The enzyme xanthine dehydrogenase acts in reverse, that is as a xanthine oxidase as a result of the higher availability of oxygen. This oxidation results in molecular oxygen being converted into highly reactive superoxide and hydroxyl radicals. Xanthine oxidase also produces uric acid, which may act as both a prooxidant and as a scavenger of reactive species such as peroxynitrite. Excessive nitric oxide produced during reperfusion reacts with superoxide to produce the potent reactive species peroxynitrite. Such radicals and reactive oxygen species attack cell membrane lipids, proteins, and glycosaminoglycans, causing further damage. They may also initiate specific biological processes by redox signaling.

Reperfusion can cause hyperkalemia.[4]

Treatment

A study of aortic cross-clamping, a common procedure in cardiac surgery, demonstrated a strong potential benefit with further research ongoing.[citation needed]

Therapeutic hypothermia

An intriguing area of research demonstrates the ability of a reduction in body temperature to limit ischemic injuries. This procedure is called therapeutic hypothermia, and it has been shown by a number of large, high-quality randomised trials to significantly improve survival and reduce brain damage after birth asphyxia in newborn infants, almost doubling the chance of normal survival. For a full review see Hypothermia therapy for neonatal encephalopathy.

However, the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermia’s ability to prevent the injuries that occur after circulation returns to the brain, or what is termed reperfusion injuries. In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns. Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during reperfusion.[5] These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patient’s inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patient’s production of deadly free radicals during reperfusion. Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain.[6]

Hydrogen sulfide treatment

There are some preliminary studies that seem to indicate that treatment with hydrogen sulfide (H2S) can have a protective effect against reperfusion injury.[7]

Ischemia/Reperfusion Protection in Obligatory Hibernators, Ground Squirrels

Obligatory hibernators such as the ground squirrels have been show to have resistance to ischemia/reperfusion (I/R) injury in liver, heart, and small intestine during the hibernation season when there is a switch from carbohydrate metabolism to lipid metabolism for cellular energy supply. [1-9] This metabolic switch limits anaerobic metabolism and the formation of lactate, a herald of poor prognosis and multi organ failure (MOF) after I/R injury. [10, 11] In addition, the increase in circulating lipids and lipid metabolism generates ketone bodies and activates peroxisomal proliferating-activated receptors (PPARs), both of which have been shown to be protective against I/R injury.

Lactate has long been an indicator of poor prognosis after I/R injury. [10, 11] Lactate is formed under anaerobic conditions when pyruvate, instead of being covered into acetyl-CoA and entering the tricarboxylic acid cycle (TCA) cycle, is converted into lactate to generate NAD+ needed for glycolysis to continue. Aside from being a marker for the level of anaerobic metabolism occurring, lactate increases interleukin- 1β (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor–α (TNF-α). [12] Multi organ failure is well known to be caused by a dysfunctional systemic inflammatory process. [11, 13] Elevated plasma levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6 indicate a poor prognosis in animal and patient studies of MOF. [11] TNFα and IL-1β mediate neutorphil infiltration into tissues and organs. [14-17] Activated neutrophils damage organs and tissue via release of protolytic enzymes, ROS, and vasoactive substances. [15, 18] These cytokines have been shown to cause lung damage in rats after I/R (hemorrhagic shock). [19]

Ketone bodies (e.g. D- betahydroxybuterate; DBHB) are produced in the liver by fatty acid β-oxidation and condensation of resulting acetyl-CoA. Ketones are known to be protective but the mechanism has not yet been elucidated. [20] Examples of their protective properties include:

  • Decreases in brain injury to neurons subject to ischemia. [21, 22]
  • Reduced oxidative stress in cardiac tissue. [23, 24]
  • Reduced oxidative stress in neurons by increasing NADH oxidation in the mitochondria and inhibiting reactive oxygen species (ROS) production. [25]
  • Increased survival time in rats after hemorrhagic shock when resuscitated with a DBHB and melatonin (an antioxidant) infusion soultion. [26]

Interestingly, when DBHB is the major energy source during hemorrhagic shock, excess lactate and H+ are inhibited. [27]

PPARs (PPARα, PPARβ, and PPARγ) are transcription factors that are activated by fatty acids (which are elevated in ground squirrels during the winter season). When activated, PPARs regulate the transcription of genes involved in lipid and carbohydrate metabolism, inflammation, and expression of mitochondrial uncoupling protein 1 (UCP-1). [28] The result of PPAR activation on metabolism is an increase fatty acid metabolism and a decrease glucose metabolism. In hibernating ground squirrels, PPARα depresses dehydrogenase pyruvate complex (PDC) via upregulation of puruvate dehydrogenase kinase 4 (PDK4), thus blocking entrance of glycolitic products into the TCA cycle. [29, 30]

Activation of PPARs also decreases inflammatory gene expression. Specifically, they suppress nuclear factor kappa-beta (NFΚB) activity and target genes of nuclear factor of activated T cells (NFAT), activator protein 1 (AP1), and signal transducers and activators of transcription (STATs). [29, 31] PPARs also block expression of inflammatory cytokines (IL-6) and have been shown to induce apoptosis of macrophages exposed to TNFα and interferon-γ. [31, 32]

Finally, activated PPARS induce the expression of mitochondrial uncoupling protein 1 (UCP-1). [29] Mitochondrial UCP-1 has the potential to reduce ROS produced via the electron transport chain (ETC) when there is a sudden burst in oxygen levels (as occurs during reperfusion). UCP-1 works by allowing hydrogen ions to reenter the mitochondrial matrix and be uncoupled from the ETC and oxygen consumption. This prevents a back up of ETC-intermediates and an increase in ROS generation.

PPARs have shown a protective role in I/R injury. Some examples include:

  • PPARγ activation reduced liver apoptosis in rats after hemorrhagic shock. [33]
  • PPARγ activation reduces systemic inflammation and lung injury after hemorrhagic shock. [34, 35]
  • PPARγ expression is altered in ground squirrel intestine during the hibernation season and may contribute to the I/R-resistant phenotype. [36]
  • During cardiac I/R, hibernating ground squirrels have reduced damage to myocardial tissue. In correlation with this, they also showed elevated PPARα-induced myocardial fatty acid utilization, reduced NFΚB activity and, reduced levels of circulating inflammatory cytokines (TNFα and IL-6). [9]

Overall hibernation-season ground squirrels show reduced injury to I/R injury. Protection from such injury may be influenced by a seasonal switch from carbohydrate to lipid metabolism resulting in a decrease in lactate formation, increase in ketone bodies, and activation of PPARs.

See also

References

  1. ^ a b Clark, Wayne M. (January 5, 2005). "Reperfusion Injury in Stroke". eMedicine. WebMD. http://www.emedicine.com/neuro/topic602.htm. Retrieved 2006-08-09. 
  2. ^ Crippen, David. "Brain Failure and Brain Death: Introduction". ACS Surgery Online, Critical Care, April 2005. Archived from the original on 2007-10-11. http://web.archive.org/web/20071011024814/http://www.acssurgery.com/abstracts/acs/acs0812.htm. Retrieved 2007-01-09. 
  3. ^ a b Mustoe T. (2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". American Journal Of Surgery 187 (5A): 65S–70S. doi:10.1016/S0002-9610(03)00306-4. PMID 15147994. 
  4. ^ John L. Atlee (2007). Complications in anesthesia. Elsevier Health Sciences. pp. 55–. ISBN 9781416022152. http://books.google.com/books?id=qVdr5MVok1YC&pg=PA55. Retrieved 25 July 2010. 
  5. ^ Adler, Jerry. “Back From the Dead.” Newsweek. July 23, 2007.
  6. ^ Polderman, Kees H. “Application of therapeutic hypothermia in the ICU.” Intensive Car Med. (2004) 30:556-575.
  7. ^ Elrod J.W., J.W. Calvert, M.R. Duranski, D.J. Lefer. "Hydrogen sulfide donor protects against acute myocardial ischemia-reperfusion injury." Circulation 114(18):II172, 2006.

References:

  1. Carey, H.V., et al., Hibernating mammals have enhanced survival and reduced gut damage after hemorrhage. Faseb Journal, 2006. 20(5): p. A1382-A1382.
  2. Dark, J., Annual lipid cycles in hibernators: integration of physiology and behavior. Annu Rev Nutr, 2005. 25: p. 469-97.
  3. Kurtz, C.C., et al., Hibernation confers resistance to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol, 2006. 291(5): p. G895-901.
  4. Lindell, S.L., et al., Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype. Am J Physiol Gastrointest Liver Physiol, 2005. 288(3): p. G473-80.
  5. Andrews, M.T., Advances in molecular biology of hibernation in mammals. Bioessays, 2007. 29(5): p. 431-40.
  6. Andrews, M.T., et al., Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor. Am J Physiol Regul Integr Comp Physiol, 2009. 296(2): p. R383-93.
  7. Carey, H.V., M.T. Andrews, and S.L. Martin, Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiol Rev, 2003. 83(4): p. 1153-81.
  8. Martin, S.L., et al., Proteomic analysis of the winter-protected phenotype of hibernating ground squirrel intestine. Am J Physiol Regul Integr Comp Physiol, 2008. 295(1): p. R316-28.
  9. Podgoreanu, M.V.M., Qing; Mackensen G. Burkhard; Zhang, Zhinquan; Smith, Michale P.; Bain, James; Newgard, Christopher B.; Khol, Franziska; Drew, Kelly L.; Barnes, Brian M.;, The Hibernator Phenotype is Cardioprotective in the Setting of Deep Hypothermic Circulatory Arrest, in American Heart Association, American Stroke Association. 2011, Duke University, University of Alaska Fairbanks: Orlando, FL.
  10. Wilson, M., D.P. Davis, and R. Coimbra, Diagnosis and monitoring of hemorrhagic shock during the initial resuscitation of multiple trauma patients: a review. J Emerg Med, 2003. 24(4): p. 413-22.
  11. Angele, M.K., C.P. Schneider, and I.H. Chaudry, Bench-to-bedside review: latest results in hemorrhagic shock. Crit Care, 2008. 12(4): p. 218.
  12. Andersson, A.K., L. Ronnback, and E. Hansson, Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures. J Neurochem, 2005. 93(5): p. 1327-33.
  13. Keel, M. and O. Trentz, Pathophysiology of polytrauma. Injury, 2005. 36(6): p. 691-709.
  14. Zerwes, H.G., et al., A multiparameter screening assay to assess the cytokine-induced expression of endothelial cell adhesion molecules. Anal Biochem, 2002. 304(2): p. 166-73.
  15. Brown, K.A., et al., Neutrophils in development of multiple organ failure in sepsis. Lancet, 2006. 368(9530): p. 157-69.
  16. Togbe, D., et al., Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury. Int J Exp Pathol, 2007. 88(6): p. 387-91.
  17. Kita, T., et al., Role of p38 mitogen-activated protein kinase pathway on heart failure in the infant rat after burn injury. Int J Exp Pathol, 2008. 89(1): p. 55-63.
  18. Boehme, M.W., P. Galle, and W. Stremmel, Kinetics of thrombomodulin release and endothelial cell injury by neutrophil-derived proteases and oxygen radicals. Immunology, 2002. 107(3): p. 340-9.
  19. Sato, H., et al., Role of tumor necrosis factor-alpha and interleukin-1beta on lung dysfunction following hemorrhagic shock in rats. Med Sci Monit, 2008. 14(5): p. BR79-87.
  20. Maalouf, M., J.M. Rho, and M.P. Mattson, The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev, 2009. 59(2): p. 293-315.
  21. Suzuki, M., et al., Beta-hydroxybutyrate, a cerebral function improving agent, protects rat brain against ischemic damage caused by permanent and transient focal cerebral ischemia. Jpn J Pharmacol, 2002. 89(1): p. 36-43.
  22. Suzuki, M., et al., Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn J Pharmacol, 2001. 87(2): p. 143-50.
  23. Veech, R.L., The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids, 2004. 70(3): p. 309-19.
  24. Veech, R.L., et al., Ketone bodies, potential therapeutic uses. IUBMB Life, 2001. 51(4): p. 241-7.
  25. Maalouf, M., et al., Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience, 2007. 145(1): p. 256-64.
  26. Klein, A.H., et al., Small-volume d-beta-hydroxybutyrate solution infusion increases survivability of lethal hemorrhagic shock in rats. Shock, 2010. 34(6): p. 565-72.
  27. Engel, F.L., M.G. Winton, and C.N. Long, Biochemical Studies on Shock : I. The Metabolism of Amino Acids and Carbohydrate during Hemorrhagic Shock in the Rat. J Exp Med, 1943. 77(5): p. 397-410.
  28. Finck, B.N., The PPAR regulatory system in cardiac physiology and disease. Cardiovasc Res, 2007. 73(2): p. 269-77.
  29. Nunn, A.V., J. Bell, and P. Barter, The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance. Nucl Recept, 2007. 5(1): p. 1.
  30. Andrews, M.T., et al., Low-temperature carbon utilization is regulated by novel gene activity in the heart of a hibernating mammal. Proc Natl Acad Sci U S A, 1998. 95(14): p. 8392-7.
  31. Bensinger, S.J. and P. Tontonoz, Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature, 2008. 454(7203): p. 470-7.
  32. Chinetti, G., et al., Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem, 1998. 273(40): p. 25573-80.
  33. Zingarelli, B., et al., Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-gamma in hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol, 2010. 298(1): p. G133-41.
  34. Zingarelli, B., et al., Lung injury after hemorrhage is age dependent: role of peroxisome proliferator-activated receptor gamma. Crit Care Med, 2009. 37(6): p. 1978-87.
  35. Chima, R.S., et al., Ciglitazone ameliorates lung inflammation by modulating the inhibitor kappaB protein kinase/nuclear factor-kappaB pathway after hemorrhagic shock. Crit Care Med, 2008. 36(10): p. 2849-57.
  36. Otis, J.P. and H.V. Carey, Hibernation alters expression of PPAR gamma in ground squirrel intestine. Faseb Journal, 2007. 21(6): p. A1319-A1319.

External links


Wikimedia Foundation. 2010.

Игры ⚽ Нужно сделать НИР?

Look at other dictionaries:

  • reperfusion injury — Damage that occurs to tissue when blood flow is restored after a period of ischaemia. The damage is caused by neutrophils that adhere to the microvasculature and release various inflammatory mediators, hydrolytic enzymes etc. as a response to… …   Dictionary of molecular biology

  • reperfusion injury — adverse effects of the restoration of blood flow following an ischemic episode, including cellular swelling and necrosis, edema, hemorrhage, the no reflow phenomenon, and tissue damage by free oxygen radicals …   Medical dictionary

  • injury — The damage or wound of trauma. [L. injuria, fr. in neg. + jus (jur ), right] blast i. tearing of lung tissue or rupture of any tissue or organ without external i., as by the force of an …   Medical dictionary

  • Hemoglobin-based oxygen carriers — At the beginning of 20th century excellent work of Landsteiner and co authors combine with significant progress in fields of heart and circulation physiology initiated development of modern transfusion medicine allowing that blood transfusion… …   Wikipedia

  • Haemoglobin-based oxygen carriers — Hemoglobin based oxygen carriers are one of two main types of oxygen carrying blood substitutes in development, the other one being perfluorocarbon emulsions. As of June 2008 there are no haemoglobin based oxygen carriers or perfluorocarbon… …   Wikipedia

  • Therapeutic hypothermia — This article is about deliberately induced cooling. For the adverse condition of Hypothermia, see Hypothermia. Therapeutic hypothermia Intervention ICD 10 PCS 6A4 OPS 301 code …   Wikipedia

  • Schrankenstörung — Störungen der Blut Hirn Schranke können durch eine Reihe von verschiedenen Erkrankungen hervorgerufen werden. Die Blut Hirn Schranke kann aber auch selbst der Ausgangspunkt für einige sehr seltene neurologische Erkrankungen sein.… …   Deutsch Wikipedia

  • Störung der Blut-Hirn-Schranke — Störungen der Blut Hirn Schranke können durch eine Reihe von verschiedenen Erkrankungen hervorgerufen werden. Die Blut Hirn Schranke kann aber auch selbst der Ausgangspunkt für einige sehr seltene neurologische Erkrankungen sein.… …   Deutsch Wikipedia

  • Erythropoetin — Oberflächenmodell von Erythropoetin (Mitte) im Komplex mit seinem Rezeptor, nach PDB  …   Deutsch Wikipedia

  • Damage associated molecular pattern molecule — Damage associated molecular pattern molecules [DAMPs] derived molecules can initiate and perpetuate immune response in the noninfectious inflammatory response. They serve as the “Signal 0” similar to pathogen associated molecular pattern… …   Wikipedia

Share the article and excerpts

Direct link
Do a right-click on the link above
and select “Copy Link”