Ischemia-reperfusion (IR) tissue injury is the resultant pathology from a combination of factors, including tissue hypoxia, followed by tissue damage associated with re-oxygenation. IR injury contributes to disease and mortality in a variety of pathologies, including

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

ischemic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop funct ...

acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both. Causes of AKI are c ...

trauma Trauma most often refers to: * Major trauma, in physical medicine, severe physical injury caused by an external source * Psychological trauma, a type of damage to the psyche that occurs as a result of a severely distressing event *Traumatic i ...

, circulatory arrest,

sickle cell disease Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red b ...

and

sleep apnea Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many tim ...

. Whether resulting from traumatic vessel disruption,

tourniquet A tourniquet is a device that is used to apply pressure to a limb or extremity in order to stop the flow of blood. It may be used in emergencies, in surgery, or in post-operative rehabilitation. A simple tourniquet can be made from a stick an ...

application, or shock, the extremity is exposed to an enormous flux in vascular perfusion during a critical period of

tissue repair Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biologi ...

and regeneration. The contribution of this ischemia and subsequent reperfusion on post-traumatic musculoskeletal tissues is unknown; however, it is likely that similar to cardiac and kidney tissue, IR significantly contributes to tissue

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

Definitions

* " Ischemia": an inadequate blood supply to an organ or part of the body. * " Reperfusion": the restoration of blood flow to an organ or tissue after having been blocked.

Mechanisms and basic science

IR and biomarkers

Serum lactate level is a proxy measure of tissue oxygenation. When tissues do not have adequate oxygen delivery (i.e., are ischemic), they revert to less efficient metabolic processes, producing lactic acid. Myoglobin is released from damaged muscle, as in the case of ischemia. Serum creatinine and BUN may be elevated in the setting of

IR and epigenetics

IR and stem cells

While some investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury, to date, none have explored the role of stem cells in muscle tissue exposed to ischemia-reperfusion injury. Stem cells have been implicated in the regeneration of skeletal muscle after traumatic and blast injuries, and have been shown to hone to muscle damaged after exercise.

Clinical implications

* Systemic effects of IR injury During periods of ischemia, cellular break down products accumulate in the local tissue. Once reperfusion occurs, these cellular products are returned to the systemic circulation, and are exposed to other organs. Organs involved in filtration (e.g., the kidneys and the liver), may be overwhelmed by the high load of cellular break down products, and face injury themselves (e.g., acute kidney injury). * Tissue swelling and

fasciotomy Fasciotomy or fasciectomy is a surgical procedure where the fascia is cut to relieve tension or pressure in order to treat the resulting loss of circulation to an area of tissue or muscle. Fasciotomy is a limb-saving procedure when used to tr ...

Following ischemia, reperfusion induces local tissue swelling. Tissue that swells within a confined space (e.g., muscle within its overlaying fascia) is susceptible to compartment syndrome in this situation. Recognizing this, surgeons frequently prophylactically release (i.e., incise) fascia of arm and leg fascial compartments after repair of a proximal vascular injury.

Tourniquets

* Pneumatic / Surgical Pneumatic, surgical tourniquets are frequently applied in the controlled environment of the operating room in order to control blood loss during an upper or lower extremity operative case. Aside from lower blood loss in itself, this improves visualization and surgical efficiency. Modern examples are found in many different sizes to accommodate different patients and sites of applications, with adult cuffs approximately 4″ wide. This distributes the pressure over, generally, a broader area than field (emergency, combat) tourniquets. The cuff is typically attached to an adjustable pneumatic pump with a built-in timer. Surgical tourniquet times in excess of two hours have been associated with an increased risk of nerve damage (e.g., neuropraxia), likely related to both direct nerve compression as well as decreased arterial inflow and oxygenation. The ischemia-reperfusion injury associated with surgical tourniquets is typically not clinically apparent when used for less than two hours. * Field / Combat Emergency field tourniquets have been used for many centuries, and have seen a resurgence in the recent combat operations in Afghanistan and Iraq, as well as expanded use in civilian trauma and mass casualty settings. Expedient and widespread tourniquet use in the modern combat setting is frequently cited as a primary driver for increased survival following major battlefield trauma. These tourniquets are often 1–2″ in width, which concentrates the pressure to a narrow band of tissue. They can result in tissue necrosis if kept in place for long periods, and should only be applied after other methods to control bleeding (e.g., elevation or direct pressure to the wound) have failed, except in settings where time does not allow waiting. Generally, tissue distal to a field tourniquet that has been in place for greater than 6 hours is considered likely to be non-viable. * Tourniquet equivalents In the same way that external compression tourniquets reduce or eliminate arterial blood flow, aortic cross clamping has the same effect. The resuscitative endovascular balloon occlusion of the aorta (REBOA) device achieves this as well. By design, these devices induce ischemia to the lower extremities (as a secondary effect, or less commonly as their primary use). Releasing the cross clamp or removing the REBOA initiates reperfusion, and IR injury to the lower extremities may follow.

Treatment approaches

Available hind limb IR animal model are either artery vein ligation or tourniquet application (by rubber band or

O-ring An O-ring, also known as a packing or a toric joint, is a mechanical gasket in the shape of a torus; it is a loop of elastomer with a round cross-section, designed to be seated in a groove and compressed during assembly between two or more par ...

). Possible treatments are the application of IR related-pathway derived drug/inhibitor and

cell therapy Cell therapy (also called cellular therapy, cell transplantation, or cytotherapy) is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-c ...

. The study has been done a role for

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

in activating necrosis. During

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

, p53 accumulates in the

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...

and triggers

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 ...

(PTP) opening. To the end of this, necrosis occurs by physical interaction with the PTP regulator cyclophilin D (CypD). The mitochondrial p53-CypD axis as an important contributor to oxidative stress-induced necrosis and implicates in disease pathology and possible treatment. Cyclosporine A, known as a potent the mitochondrial permeability transition pore (mPTP) opening inhibitor and extremely powerful in protecting cardiomyocytes from IR, normalized ROS production, decreased inflammation, and restored mitochondrial coupling during aortic cross-clamping in rat hindlimb IR model.

References

{{Reflist * Ischemia