Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

supply returns to tissue (''

re- This is a list of Latin words with derivatives in English (and other modern languages). Ancient orthography did not distinguish between ''i'' and ''j'' or between ''u'' and ''v''. Many modern works distinguish u from v but not i from j. In this a ...

'' + ''

perfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...

'') after a period of

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

or lack of oxygen (anoxia or

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

). The absence of

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...

and

nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...

s from blood during the ischemic period creates a condition in which the restoration of circulation results in

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

and

oxidative Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

damage through the induction of

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

rather than (or along with) restoration of normal function. Reperfusion injury is distinct from

cerebral hyperperfusion syndrome Cerebral hyperperfusion syndrome, also known as reperfusion syndrome, is a dysregulated state of cerebral blood flow following the restoration of arterial blood flow to the brain, usually following treatment of carotid artery stenosis. Risk factors ...

(sometimes called "Reperfusion syndrome"), a state of abnormal cerebral vasodilation.

Mechanisms

Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues. Activated endothelial cells produce more

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

but less

nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

following reperfusion, and the imbalance results in a subsequent inflammatory response. The

inflammatory response Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

is partially responsible for the damage of reperfusion injury.

White blood cell White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...

s, carried to the area by the newly returning blood, release a host of inflammatory factors such as

interleukin Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...

s as well as

free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spont ...

in response to tissue damage. The restored blood flow reintroduces oxygen within

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

s that damages cellular

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s, DNA, and the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

. 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 ''Antioxidants & Redox Signaling '' is a peer-reviewed scientific journal covering reduction–oxidation (redox) signaling and antioxidant research. It covers topics such as reactive oxygen species/reactive nitrogen species (ROS/RNS) as messenge ...

to turn on

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. White blood cells may also bind to the

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

of small

capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...

, obstructing them and leading to more ischemia. Reperfusion injury plays a major part in the biochemistry of hypoxic brain injury in stroke. Similar failure processes are involved in brain failure following reversal of

cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...

; 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 wound A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic. Chronic wounds seem to be detained in on ...

s such as

pressure sore Pressure ulcers, also known as pressure sores, bed sores or pressure injuries, are localised damage to the skin and/or underlying tissue that usually occur over a bony prominence as a result of usually long-term pressure, or pressure in combi ...

s and

diabetic foot ulcer Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot. Wound healing is an innate mechanism of action that works reliably most of the time. A key feature of wound healing is stepw ...

. 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 A wound is a rapid onset of injury that involves laceration, lacerated or puncture wound, punctured skin (an ''open'' wound), or a bruise, contusion (a ''closed'' wound) from blunt force physical trauma, trauma or compression. In pathology, a '' ...

. The main reason for the acute phase of ischemia-reperfusion injury is oxygen deprivation and, therefore, arrest of generation of ATP (cellular energy currency) by mitochondria

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

. Tissue damage due to the general energy deficit during ischemia is followed by reperfusion (increase of oxygen level) when the injury is enhanced.

Mitochondrial complex I Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the ...

is thought to be the most vulnerable enzyme to tissue ischemia/reperfusion but the mechanism of damage is different in different tissues. For example brain ischemia/reperfusion injury is mediated via complex I redox-dependent inactivation. It was found that lack of oxygen leads to conditions in which mitochondrial complex I loses its natural cofactor,

flavin mononucleotide Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as ...

(FMN) and become inactive. When oxygen is present the enzyme catalyzes a physiological reaction of

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...

oxidation by

ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...

, supplying electrons downstream of the

respiratory chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

(complexes III and IV). Ischemia leads to dramatic increase of

succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...

level. In the presence of succinate mitochondria catalyze reverse electron

transfer Transfer may refer to: Arts and media * ''Transfer'' (2010 film), a German science-fiction movie directed by Damir Lukacevic and starring Zana Marjanović * ''Transfer'' (1966 film), a short film * ''Transfer'' (journal), in management studies ...

so that fraction of electrons from succinate is directed upstream to FMN of complex I. Reverse electron transfer results in a reduction of complex I FMN, increased generation of ROS, followed by a loss of the reduced cofactor (FMNH₂) and impairment of mitochondria energy production. The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin. Reperfusion can cause

hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...

. Reperfusion injury is a primary concern in

liver transplantation Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...

surgery.

Treatment

Therapeutic hypothermia

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. 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

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.

Hydrogen sulfide treatment

There are some preliminary studies in mice that seem to indicate that treatment with

hydrogen sulfide Hydrogen sulfide is a chemical compound with the formula . It is a colorless chalcogen-hydride gas, and is poisonous, corrosive, and flammable, with trace amounts in ambient atmosphere having a characteristic foul odor of rotten eggs. The unde ...

(H₂S) can have a protective effect against reperfusion injury.

Cyclosporin

In addition to its well-known immunosuppressive capabilities, the one-time administration of

cyclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disea ...

at the time of

percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a non-surgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. The process involves combining coronary angioplasty with stenting, which is the ...

(PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with reperfusion injury published in

The New England Journal of Medicine ''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. His ...

in 2008. Cyclosporin has been confirmed in studies to inhibit the actions of

cyclophilin Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants. They are found in all domains of lif ...

D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows. However, the studies CIRCUS and CYCLE (published in September 2015 and February 2016 respectively) looked at the use of cyclosporin as a one time IV dose given right before perfusion therapy (PCI). Both studies found there is no statistical difference in outcome with cyclosporin administration. Reperfusion leads to biochemical imbalances within the cell that lead to

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...

and increased infarct size. More specifically, calcium overload and excessive production of

in the first few minutes after reperfusion set off a cascade of biochemical changes that result in the opening of the so-called

mitochondrial permeability transition pore The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP or MTP) is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stro ...

(MPT pore) in the mitochondrial membrane of cardiac cells. The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely. The cessation of energy production results in cellular death. Protecting mitochondria is a viable cardioprotective strategy. In 2008, an editorial in the New England Journal of Medicine called for more studies to determine if cyclosporin can become a treatment to ameliorate reperfusion injury by protecting mitochondria. To that end, in 2011 the researchers involved in the original 2008 NEJM study initiated a phase III clinical study of reperfusion injury in 1000 myocardial infarction patients in centers throughout Europe. Results of that study were announced in 2015 and indicated that "intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year." This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making

traumatic brain injuries A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic ...

much worse.

TRO40303

TRO40303 is a new cardioprotective compound that was shown to inhibit the MPT pore and reduce infarct size after ischemia-reperfusion. It was developed by

Trophos Trophos was a biopharmaceutical company specialising in the discovery and development of novel therapeutics to treat both orphan Neurodegenerative diseases, neurodegenerative diseases and more prevalent disorders. Trophos was founded in 1999 in ...

company and currently is in

Phase I clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

Stem cell therapy

Recent investigations suggest a possible beneficial effect of

mesenchymal stem cells Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage ce ...

on heart and kidney reperfusion injury.

Superoxide dismutase

Superoxide dismutase Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () radical into ordinary molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxygen me ...

is an effective anti-oxidant enzyme which converts superoxide anions to water and hydrogen peroxide. Recent researches have shown significant therapeutic effects on pre-clinical models of reperfusion injury after ischemic stroke.

Metformin

A series of 2009 studies published in the Journal of Cardiovascular Pharmacology suggest that

Metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...

may prevent cardiac reperfusion injury by inhibition of

Mitochondrial Complex I Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the ...

and the opening of MPT pore and in rats.

Riboflavin

In neonatal in vivo model of brain ischemia/reperfusion, tissue injury can be alleviated by the administration of FMN precursor, riboflavin that prevents inactivation of mitochondrial complex I.

Cannabinoids

A study published in 2012 show that the synthetic analogue of the

phytocannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

Tetrahydrocannabivarin Tetrahydrocannabivarin (THCV, THV, O-4394, GWP42004) is a Homology (chemistry), homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of a pentyl (5-carbon) group on the molecule, which makes it produce very differ ...

(THCV), Δ⁸-Tetrahydrocannabivarin (Δ⁸-THCV) and its

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

11-OH-Δ⁸-THCV, prevent

hepatic The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

ischaemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

/reperfusion injury by decreasing

and inflammatory responses through cannabinoid CB2 receptors and thereby decrease tissue injury and inflammation with a protective effect against liver damage. Pretreatment with a CB2

receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...

attenuated the protective effects of Δ⁸-THCV, while a CB1

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

tended to enhance it. An earlier study published in 2011 found, that

Cannabidiol Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. , clinical research on CBD incl ...

(CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response of oxidative and nitrative stress, and thereby

and tissue injury, but independent from classical CB1 and CB2 receptors.

Reperfusion protection in obligate hibernators

Obligatory hibernators such as the

ground squirrel Ground squirrels are members of the squirrel family of rodents (Sciuridae), which generally live on or in the ground, rather than trees. The term is most often used for the medium-sized ground squirrels, as the larger ones are more commonly known ...

s show 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 Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...

for cellular energy supply. This metabolic switch limits

anaerobic metabolism Anaerobic respiration is respiration using electron acceptors other than molecular oxygen (O2). Although oxygen is not the final electron acceptor, the process still uses a respiratory electron transport chain. In aerobic organisms undergoing re ...

and the formation of lactate, a herald of poor prognosis and

multi-organ failure Multiple organ dysfunction syndrome (MODS) is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis. Although Irwin and Rippe cautioned in 2005 that the use of "multiple organ failure" or "multisy ...

(MOF) after I/R injury. In addition, the increase in lipid metabolism generates

ketone bodies Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl- ...

and activates peroxisome proliferating-activated receptors (PPARs), both of which have been shown to be protective against I/R injury.

References

External links

{{DEFAULTSORT:Reperfusion Injury Cardiovascular physiology Neurotrauma