Reperfusion injury
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
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 or met with limited success 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 [6] [7] and EXPIDITION [8] [9] trials)
- Adenosine (Studied in the AMISTAD I [10] and AMISTAD II [11] trials as well as the ATTACC trial [12]). It should be noted that at high doses in anterior ST elevation MIs, adenosine was effective in the AMISTAD trial. Likewise, intracoronary administration of adenosine prior to primary PCI has been associated with imporved ehcocardiographic and clinical outcomes in one small study. [13]
- Calcium-channel blockers
- Potassium–adenosine triphosphate channel openers
- Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial [14])
- Oxygen free radical scavengers
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) - ↑ Théroux P, Chaitman BR, Danchin N; et al. (2000). "Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators". Circulation. 102 (25): 3032–8. PMID 11120691. Unknown parameter
|month=ignored (help) - ↑ Theroux P, Chaitman BR, Erhardt L; et al. (2000). "Design of a trial evaluating myocardial cell protection with cariporide, an inhibitor of the transmembrane sodium-hydrogen exchanger: the Guard During Ischemia Against Necrosis (GUARDIAN) trial". Curr Control Trials Cardiovasc Med. 1 (1): 59–67. PMC 56207. PMID 11714411.
- ↑ Bolli R (2003). "The role of sodium-hydrogen ion exchange in patients undergoing coronary artery bypass grafting". J Card Surg. 18 Suppl 1: 21–6. PMID 12691376.
- ↑ Mentzer RM, Bartels C, Bolli R; et al. (2008). "Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study". Ann. Thorac. Surg. 85 (4): 1261–70. doi:10.1016/j.athoracsur.2007.10.054. PMID 18355507. Unknown parameter
|month=ignored (help) - ↑ Mahaffey KW, Puma JA, Barbagelata NA; et al. (1999). "Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial". J. Am. Coll. Cardiol. 34 (6): 1711–20. PMID 10577561. Unknown parameter
|month=ignored (help) - ↑ Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW (2005). "A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II)". J. Am. Coll. Cardiol. 45 (11): 1775–80. doi:10.1016/j.jacc.2005.02.061. PMID 15936605. Unknown parameter
|month=ignored (help) - ↑ Quintana M, Hjemdahl P, Sollevi A; et al. (2003). "Left ventricular function and cardiovascular events following adjuvant therapy with adenosine in acute myocardial infarction treated with thrombolysis, results of the ATTenuation by Adenosine of Cardiac Complications (ATTACC) study". Eur. J. Clin. Pharmacol. 59 (1): 1–9. doi:10.1007/s00228-003-0564-8. PMID 12743668. Unknown parameter
|month=ignored (help) - ↑ Marzilli M, Orsini E, Marraccini P, Testa R (2000). "Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction". Circulation. 101 (18): 2154–9. PMID 10801755. Unknown parameter
|month=ignored (help) - ↑ Baran KW, Nguyen M, McKendall GR; et al. (2001). "Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study". Circulation. 104 (23): 2778–83. PMID 11733394. Unknown parameter
|month=ignored (help)