Ischemia-reperfusion injury of the appendicular musculoskeletal system

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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, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. [1] [2] [3] [4] Whether resulting from traumatic vessel disruption, tourniquet application, or shock, the extremity is exposed to an enormous flux in vascular perfusion during a critical period of tissue repair and regeneration. [5] [6] 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. [7] [8] [9]

Contents

Definitions

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.[ citation needed ]

Myoglobin is released from damaged muscle, as in the case of ischemia.[ citation needed ]

Serum creatinine and BUN may be elevated in the setting of acute kidney injury.[ citation needed ]

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, [10] [11] 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.[ citation needed ]

Clinical implications

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).[ citation needed ]

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.[ citation needed ]

Tourniquets

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.[ citation needed ]

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.[ citation needed ]

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.[ citation needed ]

Treatment approaches

Available hind limb IR animal model are either artery vein ligation or tourniquet application (by rubber band or O-ring). [12] [13] Possible treatments are the application of IR related-pathway derived drug/inhibitor and cell therapy. The study has been done a role for p53 in activating necrosis. During oxidative stress, p53 accumulates in the mitochondrial matrix and triggers mitochondrial permeability transition pore (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. [14] [15] 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. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Necrosis</span> Unprogrammed cell death caused by external cell injury

Necrosis is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow in, who is often regarded as one of the founders of modern pathology. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.

<span class="mw-page-title-main">Thrombosis</span> Medical condition caused by blood clots

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Ischemia</span> Restriction in blood supply to tissues

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. Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue i.e. hypoxia and microvascular dysfunction. It also implies local hypoxia in a part of a body resulting from constriction. Ischemia causes not only insufficiency of oxygen, but also reduced availability of nutrients and inadequate removal of metabolic wastes. Ischemia can be partial or total blockage. The inadequate delivery of oxygenated blood to the organs must be resolved either by treating the cause of the inadequate delivery or reducing the oxygen demand of the system that needs it. For example, patients with myocardial ischemia have a decreased blood flow to the heart and are prescribed with medications that reduce chronotrophy and ionotrophy to meet the new level of blood delivery supplied by the stenosed vasculature so that it is adequate.

<span class="mw-page-title-main">Infarction</span> Tissue death due to inadequate blood supply

Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from the Latin infarctus, "stuffed into").

<span class="mw-page-title-main">Reperfusion injury</span> Tissue damage after return of blood supply following ischemia or hypoxia

Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period 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.

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Cardioprotection includes all mechanisms and means that contribute to the preservation of the heart by reducing or even preventing myocardial damage. Cardioprotection encompasses several regimens that have shown to preserve function and viability of cardiac muscle cell tissue subjected to ischemic insult or reoxygenation. Cardioprotection includes strategies that are implemented before an ischemic event, during an ischemic event and after the event and during reperfusion. These strategies can be further stratified by performing the intervention locally or remotely, creating classes of conditioning known as remote ischemic PC (RIPC), remote ischemic PostC and remote ischemic PerC. Classical (local) preconditioning has an early phase with an immediate onset lasting 2–3 hours that protects against myocardial infarction. The early phase involves post-translational modification of preexisting proteins, brought about by the activation of G protein-coupled receptors as well as downstream MAPK's and PI3/Akt. These signaling events act on the ROS-generating mitochondria, activate PKCε and the Reperfusion Injury Salvage Kinase (RISK) pathway, preventing mitochondrial permeability transition pore (MTP) opening. The late phase with an onset of 12–24 hours that lasts 3–4 days and protects against both infarction and reversible postischemic contractile dysfunction, termed myocardial stunning. This phase involves the synthesis of new cardioprotective proteins stimulated by nitric oxide (NO), ROS and adenosine acting on kinases such as PKCε and Src, which in turn activate gene transcription and upregulation of late PC molecular players.

Kidney ischemia is a disease with a high morbidity and mortality rate. Blood vessels shrink and undergo apoptosis which results in poor blood flow in the kidneys. More complications happen when failure of the kidney functions result in toxicity in various parts of the body which may cause septic shock, hypovolemia, and a need for surgery. What causes kidney ischemia is not entirely known, but several pathophysiology relating to this disease have been elucidated. Possible causes of kidney ischemia include the activation of IL-17C and hypoxia due to surgery or transplant. Several signs and symptoms include injury to the microvascular endothelium, apoptosis of kidney cells due to overstress in the endoplasmic reticulum, dysfunctions of the mitochondria, autophagy, inflammation of the kidneys, and maladaptive repair.

Roberta Anne Gottlieb is an American oncologist, academic, and researcher. She is a Professor, and Vice-Chair of Translational Medicine in the Department of Biomedical Sciences at Cedars-Sinai Medical Center, and a Professor of Medicine at the University of California, Los Angeles.

References

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  3. ↑ Zager, R.A. & A.C. Johnson (2009). "Renal ischemia-reperfusion injury upregulates histone-modifying enzyme systems and alters histone expression at proinflammatory/profibrotic genes". Am J Physiol Renal Physiol. 296 (5): F1032–F1041. doi:10.1152/ajprenal.00061.2009. PMC   2681356 . PMID   19261745.
  4. ↑ Pincez, T.; et al. (2016). "[Pulmonary complications of sickle cell disease in children]". Arch Pediatr. 23 (10): 1094–1106. doi:10.1016/j.arcped.2016.06.014. PMID   27642150.
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  9. ↑ Kapitsinou, P.P.; et al. (2014). "Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury". J Clin Invest. 124 (6): 2396–2409. doi:10.1172/JCI69073. PMC   4092875 . PMID   24789906.
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  12. ↑ Tan, X.; et al. (2016). "Angiopoietin-2 impairs collateral artery growth associated with the suppression of the infiltration of macrophages in mouse hindlimb ischemia". J Transl Med. 14 (1): 306. doi: 10.1186/s12967-016-1055-x . PMC   5080762 . PMID   27784306.
  13. ↑ Wu, J.; et al. (2015). "Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-alphaVbeta3 integrin cross talk". Arterioscler Thromb Vasc Biol. 35 (1): 111–20. doi:10.1161/ATVBAHA.114.304554. PMC   4270947 . PMID   25378411.
  14. ↑ Vaseva, A.V.; et al. (2012). "p53 opens the mitochondrial permeability transition pore to trigger necrosis". Cell. 149 (7): 1536–48. doi:10.1016/j.cell.2012.05.014. PMC   3383624 . PMID   22726440.
  15. ↑ Alam, M.R.; D. Baetz; M. Ovize (2015). "Cyclophilin D and myocardial ischemia-reperfusion injury: a fresh perspective". J Mol Cell Cardiol. 78: 80–9. doi:10.1016/j.yjmcc.2014.09.026. PMID   25281838.
  16. ↑ Pottecher, J.; et al. (2013). "Cyclosporine A normalizes mitochondrial coupling, reactive oxygen species production, and inflammation and partially restores skeletal muscle maximal oxidative capacity in experimental aortic cross-clamping". J Vasc Surg. 57 (4): 1100–1108 e2. doi: 10.1016/j.jvs.2012.09.020 . PMID   23332985.
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