The reperfusion of an organ in ischaemia is essential for its viability and its functional recovery. But there is a flip side to this coin, the arrival of blood oxygen will cause a series of lesions; this is known as the phenomenon of ischaemia–reperfusion (I/R). Histologically, the restoration of an adequate blood flow to liver or intestines after 3 h of ischaemia followed by 1 h of reperfusion presents more parenchymatous or mucous membrane necroses than the same organ subjected to 4 h of ischaemia alone [1,2]. The arterial clamping/unclamping in vascular surgery, the use of a tourniquet in orthopaedic surgery, cardiac surgery with or without extracorporeal circulation, transplant surgery, haemorrhagic shocks, septicaemia and low blood flow states are only some examples which illustrate daily I/R in clinical practice in the operating theatre.
I/R generates an important local inflammatory reaction which affects mainly the organ concerned but can also affect two other organs. In orthopaedic surgery, the use of the tourniquet on the lower limbs affects both the lung and liver [3–5]. A small intestine I/R induces apoptotic and necrotic parenchymatous lesions in pulmonary, renal and cardiac endothelium . Organs with a high capillary density such as the lungs are more sensitive to I/R lesions. A remote I/R such as that of the splanchnic bed or a lower limb in orthopaedic surgery can induce an acute lung injury . Often, these repercussions remain subclinical but can generate a systemic inflammatory response syndrome or even multiorgan failure and lead to the death of the patient .
The vascular system and particularly the endothelium are very sensitive to I/R injuries. The endothelial cells have multiple vital duties; they control vascular tonicity and local blood flow, modulate coagulation and inflammation, intervene in the immune system, control the transfer of micro and macromolecules towards the interstitial region, convert prohormones into active hormones (angiotensin II) and intervene in the formation of new blood vessels. It is thus vital to preserve them. In the heart, the reperfusion-induced endothelial injuries contribute to myocardial depression [7,8]. The effects of I/R on the endothelium can go from the sideration of endothelial function to necrosis.
The importance and the frequency of the I/R phenomenon in clinical practice make its physiopathology of interest to anaesthesiologists. This review proposes to present to clinicians the various stages and mechanisms which make up the phenomenon of I/R. We will point out the direct effects of the deprivation of oxygen on a cell, the effects of I/R on vasomotricity, the inflammatory reaction and the production of free radicals, which it initiates, and, finally, its effects on the vascularization of an organ. It is of immediate interest to note that the physiopathology of arteriosclerosis, diabetes, cardiac insufficiency and I/R share many common attributes [9–13]. There are endogenous mechanisms of resistance to ischaemia and I/R injuries such as preconditioning and postconditioning that can appear in several conditions. These mechanisms will not be addresses in this article .
A cell in ischaemia
More than hypoxia, a more general term indicating a reduction in the supply of oxygen, ischaemia (from the Greek isch, restriction, and haema, blood) translates as a relative or absolute reduction in the blood supply to an organ. Its impact on the parenchyma will depend on its intensity, its duration, the type of cell and its metabolic needs. Oxygen is fundamental for the homeostasis of human cells. Oxidative phosphorylation, the ultimate consumer of oxygen, supplies the cell with high-energy phosphate groups in the form of ATP. The use of ATP in a large number of metabolic reactions makes the cell dependent on its oxygen supply. Within a few seconds after the interruption of blood flow, the cell consumes the oxygen contained in the oxyhaemoglobin, the myoglobin or the neuroglobin and adapts its metabolism [15,16]. Less beneficial than glycolysis coupled with oxidative phosphorylation, anaerobic glycolysis, mainly supplied by glycogenolysis, maintains a minimal production of ATP. Nevertheless, demand quickly exceeds production, and the intracellular concentration of ATP decreases. The accumulation of lactate and protons and the reduction in the oxidation of nicotinamide adenine dinucleotide phosphate (NADPH2) by mitochondria acidifies the cell and also inhibits anaerobic glycolysis . When there is a lack of ATP, the cell will erode diphosphate adenosine from AMP and finally adenosine AMP that can diffuse freely out of the cell, decreasing the cellular pool of adenine nucleotide, the precursor of ATP . Adenine nucleotide deficiency will slow down the synthesis of ATP at the time of reperfusion.
The functioning of the ATP-dependent membrane pumps is profoundly disturbed by the depletion in ATP. Reduction in the activity of the Na+/K+/ATPase pump supports the increase in the intracellular sodium concentration. Stimulation of the antiport Na+/H+ through cellular acidosis worsens the sodium overload and affects the operation of other membrane conveyors such as the Na+/Ca2+ antiport [18–20]. The Na+/Ca2+ antiport allows sodium extrusion from the cell depending on the intracellular accumulation of calcium (Fig. 1). Cellular hypercalcaemia induces the degradation of sarcoplasmic phospholipids and cytoskeleton protein, modifies calcium affinity and the effectiveness of contractile proteins and modifies the tertiary structure of some enzymes such as xanthine dehydrogenase to xanthine oxidase [21–23]. These two enzymes catalyse the same reactions, namely the transformation of hypoxanthine in xanthine and xanthine in uric acid. But whereas the first uses nicotinamide adenine dinucleotide (NAD+) as a cofactor, the second uses oxygen and forms the anion superoxide, a free radical that will be produced massively with reperfusion.
Mitochondrial hypercalcaemia, secondary to the cellular hypercalcaemia, induces a mitochondrial oedema, disturbs the supramolecular structures (oxidative phosphorylation) located in the internal membrane of the mitochondrion and abolishes its membrane potential (ΔΨm). The loss of ΔΨm is accompanied by the opening of the permeability transition pore (PTP) in the mitochondrion and is irreversible. This broad nonspecific channel lets through molecules of a molecular weight of more than 1500 Da and allows them to escape the mitochondrial matrix, which compromises the survival of mitochondria. Mitochondrial calcium overload is a major trigger of the opening of the PTP [24–26].
Finally, the reduction in the intracellular concentration of ATP prevents regeneration of glutathione, ascorbic acid and tocopherol that take part in the detoxication of the metabolites present in the cytosol and in the sarcoplasmic membrane. The accumulation of osmotically activate particles such as lactate, sodium, inorganic phosphate and creatine leads to an oedema of the cell .
A cell in ischaemia secretes and expresses a multitude of substances and proteins on its surface. For example, bradykinin, noradrenaline, angiotensin, adenosine, acetylcholine or opioids are secreted by cardiomyocytes in ischaemia [27–29]. All of these substances are triggers for preconditioning. This attempt at adaptation and protection will be effective only under certain conditions. The adenosine secreted by the cells reinforces the intercellular junctions and cohesion. Ischaemia stimulates expression on the surface of the endothelial cells of the leucocyte molecules of adhesion [P-selectins, L-selectins, the intercellular adhesion molecule and platelet–endothelial cell adhesion molecules (PECAMs)], the secretion of cytokines [tumour necrosis factor-α (TNFα), interleukin (IL)-1, 6, 8 and others] and of vasoactive agents (endothelin and thromboxane A2) [30–33]. The cytokines, whose production will explode at the time of reperfusion, initiate the inflammatory response. Meanwhile, the surface adhesion proteins affect the concentration of neutrophils in the interstitium. Well before being a mechanism of aggression, neutrophils are necessary for healing inflamed tissue. The neutrophils take part in the removal of necrosed tissue at the time of ischaemia. In summary, the main cellular effects of hypoxia are as follows:
- cellular acidosis;
- loss of sarcoplasmic membrane potential;
- cellular swelling;
- cytoskeleton disorganization;
- reduction of ATP and phosphocreatine is more than the reduction in the energy substrates;
- reduction of glutathione, of α-tocopherol;
- increasing expression of leucocyte adhesion molecules;
- secretion of cytokines (TNFα, IL-1, 6, 8 and others).
The reestablishment of a blood flow in an ischaemic area restores the aerobic metabolism and supports the recovery of tissue but will be accompanied by significant lesions. The vasomotricity and the endothelial functions will be deeply affected by it. Reperfusion will be accompanied by an important inflammatory response, characterized by the activation of the complement and the polymorphonuclear leucocyte neutrophils and a massive production of free radicals. The proinflammatory state induced by reperfusion continues for several days [34,35]. Lastly, the oxidative stress, the production of cytokines and the secondary mitochondrial lesions with reperfusion will induce apoptosis on the level of the parenchyma and the vascular structures.
Vasomotricity and ischaemia–reperfusion
Basic vascular tonicity is a continual balance between the influences of vasoconstrictors and vasodilatators. Endothelium and the smooth musculature play a vital part in its control. The conservation of a qualified vasomotricity improves postischaemic recovery of an organ.
Many studies have shown that posthypoxic vasoconstriction as well as endothelium-independent vasodilatation are slightly deteriorated by I/R, whereas endothelium-dependent vasodilatation is significantly affected [36–38]. These results demonstrate a higher resistance to ischaemia in the vascular smooth musculature than in the endothelium.
Early endothelial dysfunction is, above all, present at the level of small-calibre vessels, appears with the reperfusion and persists for 4–12 weeks [38–41]. It is the reperfusion that induces the endothelial dysfunction. Coronary arteries of dogs subjected to ischaemia without reperfusion do not present an endothelial dysfunction . To explain this phenomenon, several hypotheses have been proposed: a massive production of free radicals, a deficit of dihydrobiopterin [an essential cofactor of nitric oxide synthase (NOS)], a too high consumption of arginine in the pathways other than that of NOS or the production of the C5b-9 fraction of the complement [31,42–46]. The beneficial effect on early endothelial dysfunction by the administration of antibody anti-TNFα or the reduction in the production of TNFα obtained by chelating the free radicals at the time of the reperfusion has encouraged certain authors to consider TNFα as one of the keys to this phenomenon [12,47–49]. The significant production of TNFα seems paramount. It supports its own production via nuclear factor (NF)-κB, decreases the production of nitric oxide and stimulates the production of free radicals by activating xanthine oxidase and NADPH2 oxidase by way of ceramide/sphingosine kinase [12,48,49].
The superoxide anion (•O−), produced by the xanthine oxidase, and nitric oxide react to produce a reactive nitrogen species peroxynitrite (ONOO−). What decreases the nitric oxide bioavailability and aggravates cellular damage? The loss of output of nitric oxide explains the loss of the endothelial vasodilatation dependent on the posthypoxic endothelium. The late endothelial dysfunction, observed in the weeks that follow reperfusion, seems to be related to phenotypical modifications of the new endothelial cells .
The inflammatory response
If the inflammatory response affects the body's main organ or the area of the body concerned with the reperfusion, in putting into the circulation many cytokines, chemokines and proinflammatory metabolites, the inflammation is extended to the whole body. The repercussions of this proinflammatory state will vary from one organ to another and will depend on the intensity of the initial inflammation. An organ such as the lung, with a raised capillary density, is particularly vulnerable [3,5]. Activated neutrophils infiltrate the parenchyma of other organs that have undergone ischaemia and cause further injuries. The functional repercussions of the organ range from momentary dysfunction to organ failure. The inflammatory response induced by the reperfusion is characterized by the activation of the complement and the polymorphonuclear leucocyte neutrophils.
Activation of complement
I/R activates the complement and the formation of many inflammatory mediators, including the anaphylatoxins C3a, C4a and C5a. These recruit and stimulate the inflammatory cells and increase the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin on the surface of the endothelium and the neutrophils [31,50]. C5a is a chemotactic factor that directly stimulates the synthesis and the leucocyte secretion of cytokines such as IL-1 and 6, the monocytes chemoattractive protein-1 (MCP-1) and TNFα. The iC3b takes part in the adhesion of the neutrophils on the endothelium. C5b-9, known as the ‘final cytolytic membrane attack complex complement’, is a powerful chemotactic agent, which causes direct lesions to the endothelial cells, stimulates the endothelial production of IL-8, MCP-1 and reactive oxygen species (ROS) and inhibits endothelium-dependent vasodilatation [31,50].
The neutrophil–endothelium interaction
The neutrophils play a central part in the inflammatory response and the genesis of the lesions related to reperfusion. Their activation and that of the endothelium by cytokines (IL-6, TNFα, IL-8, IL-1β and others) and of the proinflammatory mediators [platelet-activating factor (PAF), free radicals and others] will allow a narrow interaction between them that will result in a significant concentration of neutrophils activated in the interstitium [23,33,51–53]. This interaction takes place in three parts: a weak adhesion of the neutrophils to the endothelium, followed by a stronger adhesion and, finally, the neutrophil migration (Fig. 2). Three families of adhesion molecules are implicated: selectins, β2-integrins and immunoglobulins.
The selectins are surface glycoproteins implicated in weak adhesion. The L-selectin, expressed by the endothelial cells and the neutrophils, plays a part at the beginning of reperfusion. It interacts with the P-selectin on the neutrophils and a specific ligand present on the membrane of the neutrophil, the E-selectin-specific ligand-1 (ESL-1) . Endothelial P-selectin will be expressed later from the Weibel–Palade bodies after activation of the endothelium by ROS, hypercalcaemia, complement or thrombin. Its peak of expression occurs 10–20 min after the beginning of reperfusion . It interacts with P-selectin glycoprotein ligand-1 (PSGL-1) expressed by the neutrophils. These interactions are very weak, giving the neutrophils a weak, transitory, reversible adhesion known as ‘leucocyte rolling’. This phase prepares the neutrophil and the endothelium for the following stage. A more important stowing of neutrophils in the endothelium utilizes other leucocyte and endothelium proteins that have a stronger affinity for each other.
The ROS, PAF and leucotriene (LTB4) stimulate the expression by neutrophils of β2-integrins from the intracellular granules. This family of membrane proteins consists of CD11a/CD18, CD11b/CD18 and CD11c/CD18 and interacts with the ICAM-1 endothelial protein whose expression is enhanced by TNFα and IL-1 [55,56]. This interaction fastens the neutrophil to the surface of the endothelial cell and allows the next stage.
ICAM-1 and PECAM-1 are adhesion molecules belonging to the superfamily of immunoglobulins which take part and orchestrate the transfer of the neutrophils towards the interstitium. The leucocyte extravasation utilizes many stages, not all of which are yet clear. Nevertheless, it seems that PECAM-1, localized at the level of the intercellular endothelial junctions, is necessary to allow neutrophil migration . This transfer is facilitated by the inflammation mediators, the connection of CD11/CD18–ICAM-1 and the ROS making the endothelial barrier receptive by decreasing the expression of cadherin and phosphorylation of vascular endothelial cadherin and cathenin, components of the intercellular junctions [58–61] (Fig. 2).
Arriving at the interstitium, the activated neutrophil will cause considerable damage to a tissue, which has already suffered from hypoxia. These lesions are mainly related to the massive ROS production, to the release of the contents of the neutrophilic granules and to the metabolites of arachidonic acid. The last, metabolized by phospholipase A2, generates PAF and LTB4, two powerful chemoattractive components that stimulate the adhesion of neutrophils to the endothelium and their degranulation in the interstitium. The neutrophilic granules, filled with proteases, collagenases, elastases, lipooxygenases, phospholipases and myeloperoxidases, will digest and disorganize the protein network of extracellular matrix. The proteic network of extracellular matrix is important in healing while being used to guide tissue formation. For example, elastase is able to digest substrates such as collagen types III and IV, immunoglobulins, fibronectin and proteoglycans. Certain cells such as the cardiomyocytes, stimulated by the IL-6 that they produce at the time of ischaemia, express ICAM-1. The neutrophil binds to this receiver and empties the contents of its granules into direct contact with the cellule [62,63].
The inflammation induced by reperfusion is a major cause of the lesions observed after restoration of blood flow in an ischaemic organ. The massive production of cytokines, the activation of the complement and a complex choreography of the neutrophils are the key factors and are therefore being examined in research to modulate the inflammatory reaction. Although many therapeutic trials have shown their effectiveness on animals under laboratory conditions, clinical experiments show more modest results [64–69]. A recent review by Yellon and Hausenloy  shows that the various tests applying to the modulation of inflammation induced by reperfusion in human heart do not influence the size of the infarction, functional recovery postinfarction or the incidence of clinical postinfarction events such as death or cardiac insufficiency [70–73].
The oxygen-free radicals (ROS) such as anion superoxide (•O2−), hydrogen peroxide (H2O2) and the radical hydroxyl (OH−) as well as the reactive nitrogen oxide species (RNOS) are implicated in the tissue lesions of reperfusion. All these molecules present an unpaired electron on their last electron shell. This characteristic makes them aggressive and highly reactive with respect to the various cellular components. The massive production of ROS quickly exceeds the capacity of the cellular defence systems (catalase, superoxide dismutase, glutathione peroxidase and the vitamins C and E) and pushes the cell into an important oxidative stress. NADPH oxidase, xanthine oxidase, the disruption of the respiratory chain and the pathways for arachidonic acid are the principal sources of ROS [74–76]. In reperfused tissue, only the first two seem particularly implicated. The anion superoxide formed by the NADPH oxidase or the xanthine oxidase is quickly transformed into H2O2 by the superoxide dismutase, which in the presence of iron (Fe2+) or copper (Cu+) gives a radical hydroxyl.
The neutrophils have in their sarcoplasmic membrane a NADPH oxidase system that produces superoxide anions in the phagocytosis pits and in the external environment. The simultaneous secretion of myeloperoxidase by exocytosis of the azurophil grains catalyses the formation of hypochloric acid in the presence of halides. While reacting with nitric oxide, the anion superoxide produces peroxynitrite.
The PAF, TNFα, IL-6, IL-1β, granulocyte–macrophage colony-stimulating factor, fraction C5a of the complement and the ROS themselves stimulate endothelial ROS production [57,77,78]. The ROS activate NF-κB and neutrophils, stimulating cytokinic production (TNFα, IL-6, PAF and others), the expression of adhesion molecules and the adhesion of the endothelium surface .
The reperfusion of an ischaemic organ generates an oxidative stress. The NADPH2 oxidase of the neutrophils, xanthine oxidase and the dysfunctioning of mitochondrial oxidative phosphorylation are the principal producers of free radicals at the time of reperfusion. The direct action of the ROS with regard to the cellular and indirect structures shows them to be potential therapeutic targets to decrease the reperfusion lesions. The administration of endogenous antioxidants was largely investigative in the prevention of I/R lesions. In animal studies [79–82], the administration at the time of the reperfusion of enzymes such as superoxide dismutase or catalase, chelating agents such as desferrioxamine or mannitol, antioxidant agents such as vitamins C and E or inhibitors of xanthine oxidase, such as allopurinol, decrease the impact of ROS. However, human studies [83–87] show that results are more mitigated, which limit their therapeutic use.
Reperfusion is vital for the functional recovery of an organ in ischaemia but also initiates the apoptosis pathways [88,89]. Apoptosis is an active mechanism of cellular death, genetically programmed, energy-consuming, and requiring the expression or activation of specific enzymes, which can be induced by the oxidative stress of reperfusion. The reperfusion-induced apoptosis was highlighted in many organs including the heart, the brain, kidney or liver. The reperfusion of an organ can induce apoptosis in another distant organ. For example, reperfusion of a lower limb or small bowel can induce apoptosis at the level of the cardiomyocytes or the lung, respectively [90,91]. TNFα production by the reperfused organ seems to play a crucial part [88,92–94]. TNFα is able to initiate a receptor-dependent death pathway by activating downstream caspases [88,94,95]. But, the TNFα pathways are not the only cause. The oedema and the depolarization of mitochondria, along with hypercalcaemia, release into the cytoplasm proteins such as cytochrome C. When this protein, which is a constituent of the respiratory chain, is released from the mitochondria into the cytoplasm, it interacts with apoptotic protease activating factor-1 (Apaf-1) and ATP to form the apoptosome, a large oligomeric protein complex that can activate caspase 9, which activates the caspases pathway.
The apoptosis of the endothelium is earlier than that in the subjacent parenchyma and influences it . Thus, a reduction in the endothelial apoptosis decreases that of the subjacent cardiomyocytes. This shows that signals emanating from the endothelium in apoptosis can induce or reinforce those in the cardiomyocytes.
Integration of different effects of ischaemia–reperfusion
According to the stage of the vascular system considered (small arteries, capillaries and postcapillary veins), the repercussions of I/R are identical, but the clinical pictures differ.
At the arteriolar level
The principal manifestation of I/R on arterioles is the loss of the vasodilatation-dependent endothelium and the appearance of spasms . The wide endothelial lesions decrease the production of nitric oxide and no longer counterbalance the tendency to vasoconstriction of the arterioles. This tendency is highlighted in several tissues such as in the skeletal muscles, the heart, lungs or the brain [98–101]. The effects on the arteriole vasomotricity from a combination of I/R and inflammation are well documented in cardiac surgery. The increase in the contractile response of the pulmonary and mesenteric microcirculation after cardiac surgery predisposes the development of a pulmonary shunt or mesenteric ischaemia, particularly during the administration of vasopressive drugs in postextracorporeal circulation [102,103].
At the capillary level
The posthypoxic recovery of an organ depends on the quality of its microcirculation for nutrients and gaseous exchange. However, it is the seat of a paradoxical phenomenon called ‘no reflow’, which is characterized by a major reduction in the capillary density. Despite the reestablishment of complete blood flow, an incomplete and heterogeneous perfusion on the level of the microcirculation persists [104,105]. The capillaries are blocked by the parenchymatous and endothelial oedema and the adhesion of the neutrophils and platelets to the surface of the endothelium, aided by the reduction in the production of nitric oxide [100,104–107]. ROS and the depletion of ATP modify the cytoskeleton and the intercellular junctions, aiding the loss of liquid from the vascular bed towards the interstitium [108,109]. The phenomenon of no reflow persists for several weeks after reperfusion .
At the postcapillary veins level
The postcapillary veins are the seats of the inflammatory reaction. Supported by a slower blood flow, the margination and extravasation of the leucocytes are made easier. Venous blood, arriving from the reperfused zones, is rich in proinflammatory mediators and activated neutrophils. They cause lesions both directly and indirectly through their interactions with the platelets [106,110]. Endothelial lesions do not allow the intravascular oncotic pressure to recover the excess liquid from the interstitium, increasing oedema and contributing to the phenomenon of ‘no reflow’. These states are very similar to those seen during endotoxaemia, sepsis with organ dysfunction or with burns [111–113].
Surgery-induced I/R injuries present a similar physiopathology between organs. Repercussions for the organ's function depend on the degree and duration of the ischaemia and also on the sensitivity of the organ. Repercussions for the general functioning of the body are going to depend on the role of the organ in the homeostasis and on the impact of the ischaemia on its function.
In pulmonary transplantation surgery, I/R-induced lung injury is characterized by nonspecific alveolar damage, lung oedema and hypoxaemia. The most severe form may lead to primary graft failure and remains a significant cause of morbidity and mortality after lung transplantation .
Cardiopulmonary bypass during cardiac surgery and lung resection can also induce apoptosis and I/R-induced lung injury [115–117]. Such an increase in pulmonary microvascular permeability appears to have a bimodal pattern peaking at 30 min and 4 h after reperfusion . Mechanical ventilation, often indispensable in support of patients with respiratory failure, general anaesthesia or lung transplantation, increases I/R-induced lung injuries .
The kidney is also sensitive to I/R. The development of perioperative acute renal failure is associated with a high incidence of morbidity and mortality. This incidence varies according to different surgical procedures . For example, acute renal failure is the most important complication of remote tissue damage following abdominal aortic surgery . I/R modifications disrupt the harmonious functioning of the kidney, induce renal tubular injuries and contribute to the decrease glomerular filtration.
Recent data suggest that 13% of patients with acute kidney injury (AKI) progress to end-stage renal disease within 3 years. In patients with preexisting renal disease, the progression to end-stage renal disease increases to 28% within the same period . These results suggest that AKI predisposes to chronic renal complications. I/R reduces blood vessel density and promotes renal fibrosis. This reduction may predispose patients to the development of chronic kidney disease. The mechanisms mediating vascular loss are not clear but may be related to the lack of effective vascular repair responses .
In cardiac surgery and in myocardial ischaemia, cell death following I/R has been reported to have features of apoptosis and necrosis. The loss of cardiomyocytes, hibernating, in ‘no reflow’ zones, and stunning, led by the free radicals and the calcium overload, explain the contractile posthypoxic dysfunction. The stunned cardiomyocytes can return to function after a variable period of several hours or days. Intracellular ionic perturbation favours ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia or ventricular extrasystole . During ischaemia, cardiomyocytes express ICAM-1. The neutrophil binds to this receiver and empties the contents of its granules into direct contact with the cells [62,63].
The mechanisms of I/R-induced brain injury have many similar aspects to those of myocardial I/R-induced injury. Many mediators and cytokines produced by the I/R such as bradykinin, purine nucleotides, nitric oxide or ROS increase the blood–brain barrier permeability and induce cerebral oedema . Although leucocyte infiltrations into the ischaemic brain increase cerebral damage, accumulation of leucocytes in the microcirculation reduces reperfusion and increases the ‘no reflow’ phenomenon.
The indirect repercussions of I/R on organs remote from the reperfused site are much more insidious. Neutrophils and the means of complement activation, with a massive production of cytokines/chemokines, promote a proinflammatory state affecting the functioning of other organs. During abdominal aortic surgery, I/R injuries are not only limited to the lower extremities but also cause damage in remote organs and tissues such as the lungs, kidneys, heart and intestines [121,125–128]. Lung injuries following abdominal aortic aneurysm surgery are characterized by progressive hypoxaemia, pulmonary hypertension, decreased lung compliance and nonhydrostatic pulmonary oedema, consistent with adult respiratory distress syndrome [125,128]. In comparison with surgery, endovascular abdominal aortic aneurysm repair decreases I/R and I/R-induced intestinal mucosal, renal and pulmonary dysfunction .
Within other contexts, several studies support the hypothesis that revascularization of critically ischaemic limbs leads to intestinal mucosal barrier dysfunction and cytokine release and suggest that the magnitude of the inflammatory response following I/R injury is related to the degree of initial ischaemia . Lower limb reperfusion can induce apoptosis of cardiomyocytes . Revascularization of ischaemic bowel leads to significant multiple organ dysfunctions such as in liver, kidney, lung and haemostasis, potentially as a result of intestinal I/R injury . In cardiac surgery, I/R could contribute to the postoperative cognitive disturbance .
For patients presenting with organ ischaemia, fast and complete reperfusion is the most effective means to improve the clinical outcome. However, clinicians know that, although restoring circulation, this will generate a local and systemic inflammation, which in its most severe form can lead to multiorgan failure and the death of the patient.
Arterial, cardiac and transplant surgery, haemorrhagic shock and low-output heart failure episodes met daily in operating theatres and ICUs represent a few examples. The physiology of these lesions is complex and is characterized by a massive production of ROS, a vigorous inflammatory reaction with neutrophil activation, and foremost is played out at the level of the endothelial cell. The presence in the blood circulation of cytokines and proinflammatory mediators arriving from the reperfused areas activates the endothelium of distant organs. It is challenging that the use of a tourniquet in orthopaedic surgery has effects on the exchange of pulmonary gases or on renal function.
A better knowledge of the mechanisms of endogenous protection, particularly the mechanisms of action of reperfusion injury salvage kinases or the blockage of the opening of the mitochondrial transitory pore of permeability, would allow the development of new pharmacological strategies in the management of I/R lesions. Interindividual variations, associated disorders, medications and the variability in the durations of ischaemia can explain why, until recently, human clinical studies have had difficulty in confirming the positive results obtained in animal research in the treatment of I/R lesions.
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