Reperfusion injury: Difference between revisions
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==Mechanisms of reperfusion injury== | ==Mechanisms of reperfusion injury== | ||
The damage of reperfusion injury is due in part to the [[inflammatory response]] of damaged tissues. [[White blood cell]]s carried to the area by the newly returning blood release a host of [[cytokine|inflammatory factors]] such as [[interleukin]]s as well as [[reactive oxygen species|free radicals]] in response to tissue damage | The damage of reperfusion injury is due in part to the [[inflammatory response]] of damaged tissues. [[White blood cell]]s carried to the area by the newly returning blood release a host of [[cytokine|inflammatory factors]] such as [[interleukin]]s as well as [[reactive oxygen species|free radicals]] in response to tissue damage | ||
<ref name="WMClark">{{cite web | last = Clark | first = Wayne M. | title = Reperfusion Injury in Stroke | work = eMedicine | publisher = WebMD | date = January 5, 2005 | url = http://www.emedicine.com/neuro/topic602.htm | accessdate = 2006-08-09 }}</ref>.The restored blood flow reintroduces oxygen within [[cell (biology)|cell]]s that damages cellular [[protein]]s, [[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 build up in small [[capillary|capillaries]], obstructing them and leading to more ischemia<ref name="WMClark" />. | <ref name="WMClark">{{cite web | last = Clark | first = Wayne M. | title = Reperfusion Injury in Stroke | work = eMedicine | publisher = WebMD | date = January 5, 2005 | url = http://www.emedicine.com/neuro/topic602.htm | accessdate = 2006-08-09 }}</ref>.The restored blood flow reintroduces oxygen within [[cell (biology)|cell]]s that damages cellular [[protein]]s, [[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 build up in small [[capillary|capillaries]], obstructing them and leading to more ischemia<ref name="WMClark" />. Other pathophysiologic disturbances include intracellular calcium overload and the opening of mitochondrial permeability transition pores. <ref name="pmid14962470">{{cite journal |author=Halestrap AP, Clarke SJ, Javadov SA |title=Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection |journal=Cardiovasc. Res. |volume=61 |issue=3 |pages=372–85 |year=2004 |month=February |pmid=14962470 |doi=10.1016/S0008-6363(03)00533-9 |url=http://cardiovascres.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=14962470}}</ref> | ||
In prolonged ischemia (60 minutes or more), [[hypoxanthine]] is formed as breakdown product of [[Adenosine triphosphate|ATP]] metabolism. The enzyme ''[[xanthine dehydrogenase]]'' is converted to ''[[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]] [[Radical (chemistry)|radicals]]. Xanthine oxidase also produces [[uric acid]], which may act as both a prooxidant and as a scavenger of reactive species such as peroxinitrite. 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]]. | |||
==Specific organs affected by reperfusion injury== | |||
===The central nervous system=== | |||
Reperfusion injury plays a part in the [[brain]]'s [[ischemic cascade]], which is involved in [[stroke]] and [[brain trauma]]. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to [[wound healing|heal]] of [[chronic wound]]s such as [[pressure sore]]s and [[diabetic foot]] [[ulcer]]s<ref name="TMustoe">{{cite journal | author=Mustoe T. | title=Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy | journal=AMERICAN JOURNAL OF SURGERY | volume=187 | issue=5A | year=2004 | pages=65S-70S | id=PMID 15147994}}</ref>. 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]]<ref name="TMustoe" />. | Reperfusion injury plays a part in the [[brain]]'s [[ischemic cascade]], which is involved in [[stroke]] and [[brain trauma]]. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to [[wound healing|heal]] of [[chronic wound]]s such as [[pressure sore]]s and [[diabetic foot]] [[ulcer]]s<ref name="TMustoe">{{cite journal | author=Mustoe T. | title=Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy | journal=AMERICAN JOURNAL OF SURGERY | volume=187 | issue=5A | year=2004 | pages=65S-70S | id=PMID 15147994}}</ref>. 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]]<ref name="TMustoe" />. | ||
===The myocardium=== | |||
Restoration of epicardial patency can be associated with reperfusion injury in the myocardium. Many therapies have failed to improve reperfusion injury. Pharmacotherapies that have failed include: <ref name="pmid17306241">{{cite journal |author=Dirksen MT, Laarman GJ, Simoons ML, Duncker DJ |title=Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies |journal=Cardiovasc. Res. |volume=74 |issue=3 |pages=343–55 |year=2007 |month=June |pmid=17306241 |doi=10.1016/j.cardiores.2007.01.014 |url=http://cardiovascres.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17306241}}</ref> | |||
#[[Beta-blockade]] | |||
#GIK (glucose-insulin-potassium infusion) (Studied in the | |||
Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II <ref name="pmid16631017">{{cite journal |author=Timmer JR, Svilaas T, Ottervanger JP, ''et al'' |title=Glucose-insulin-potassium infusion in patients with acute myocardial infarction without signs of heart failure: the Glucose-Insulin-Potassium Study (GIPS)-II |journal=J. Am. Coll. Cardiol. |volume=47 |issue=8 |pages=1730–1 |year=2006 |month=April |pmid=16631017 |doi=10.1016/j.jacc.2006.01.040 |url=http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(06)00178-1}}</ref> | |||
#Sodium-hydrogen exchange inhibitors such as [[cariporide]] (Studied in the GUARDIAN and EXPIDITION trials) | |||
#[[Adenosine]] (Studied in the AMISTAD trials) | |||
#[[Calcium-channel blockers]] | |||
#Potassium–adenosine triphosphate channel openers | |||
#Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial) | |||
#Oxygen free radical scavengers | |||
Recent trials, with a monoclonal antibody directed against complement C5 (6) and a protein kinase C inhibitor (7), were disappointing. Adenosine reduced anterior infarct size when used at high doses (8); however, a review of 5 trials (including the AMISTAD [Acute Myocardial Infarction Study of Adenosine] I and II studies) failed to show significant benefit (5). In a report of 2 studies, atrial natriuretic peptide reduced infarct size as estimated by creatine kinase (9). The work in this field has been comprehensively summarized (5). In controlled trials, post-conditioning (10) and cyclosporine (11) reduced infarct size. | |||
==Treatment== | ==Treatment== | ||
Revision as of 15:16, 4 March 2009
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Overview
Reperfusion injury refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood 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.
Mechanisms of reperfusion injury
The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. 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 build up in small capillaries, obstructing them and leading to more ischemia[1]. Other pathophysiologic disturbances include intracellular calcium overload and the opening of mitochondrial permeability transition pores. [2]
In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product of ATP metabolism. The enzyme xanthine dehydrogenase is converted to 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 peroxinitrite. 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.
Specific organs affected by reperfusion injury
The central nervous system
Reperfusion injury plays a part in the brain's ischemic cascade, which is involved in stroke and brain trauma. 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].
The myocardium
Restoration of epicardial patency can be associated with reperfusion injury in the myocardium. Many therapies have failed to improve reperfusion injury. Pharmacotherapies that have failed include: [4]
- Beta-blockade
- GIK (glucose-insulin-potassium infusion) (Studied in the
Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II [5]
- Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN and EXPIDITION trials)
- Adenosine (Studied in the AMISTAD trials)
- Calcium-channel blockers
- Potassium–adenosine triphosphate channel openers
- Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial)
- Oxygen free radical scavengers
Recent trials, with a monoclonal antibody directed against complement C5 (6) and a protein kinase C inhibitor (7), were disappointing. Adenosine reduced anterior infarct size when used at high doses (8); however, a review of 5 trials (including the AMISTAD [Acute Myocardial Infarction Study of Adenosine] I and II studies) failed to show significant benefit (5). In a report of 2 studies, atrial natriuretic peptide reduced infarct size as estimated by creatine kinase (9). The work in this field has been comprehensively summarized (5). In controlled trials, post-conditioning (10) and cyclosporine (11) reduced infarct size.
Treatment
Glisodin, a dietary supplement derived from superoxide dismutase (SOD) and wheat gliadin, has been studied for its ability to mitigate ischemia-reperfusion injury. A study of aortic cross-clamping (a common procedure in cardiac surgery), demonstrated a strong potential benefit with further research ongoing.
See also
References
- ↑ 1.0 1.1 Clark, Wayne M. (January 5, 2005). "Reperfusion Injury in Stroke". eMedicine. WebMD. Retrieved 2006-08-09.
- ↑ Halestrap AP, Clarke SJ, Javadov SA (2004). "Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection". Cardiovasc. Res. 61 (3): 372–85. doi:10.1016/S0008-6363(03)00533-9. PMID 14962470. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 Mustoe T. (2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". AMERICAN JOURNAL OF SURGERY. 187 (5A): 65S–70S. PMID 15147994.
- ↑ Dirksen MT, Laarman GJ, Simoons ML, Duncker DJ (2007). "Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies". Cardiovasc. Res. 74 (3): 343–55. doi:10.1016/j.cardiores.2007.01.014. PMID 17306241. Unknown parameter
|month=ignored (help) - ↑ Timmer JR, Svilaas T, Ottervanger JP; et al. (2006). "Glucose-insulin-potassium infusion in patients with acute myocardial infarction without signs of heart failure: the Glucose-Insulin-Potassium Study (GIPS)-II". J. Am. Coll. Cardiol. 47 (8): 1730–1. doi:10.1016/j.jacc.2006.01.040. PMID 16631017. Unknown parameter
|month=ignored (help)