Nerve injury
Nerve injury is an injury to a nerve. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve.[1] Usually, however, nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.[2]
"Nerve damage" redirects here. For the Skinlab album, see Nerve Damage.Nerve injury
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Unlike in the central nervous system, neuroregeneration in the peripheral nervous system is possible.[2][3][4] The processes that occur in peripheral regeneration can be divided into the following major events: Wallerian degeneration, axon regeneration/growth, and reinnervation of nervous tissue. The events that occur in peripheral regeneration occur with respect to the axis of the nerve injury. The proximal stump refers to the end of the injured neuron that is still attached to the neuron cell body; it is the part that regenerates. The distal stump refers to the end of the injured neuron that is still attached to the end of the axon; it is the part of the neuron that will degenerate, but the stump remains capable of regenerating its axons.
The study of nerve injury began during the American Civil War and greatly expanded during modern medicine with such advances as use of growth-promoting molecules.[5]
Overview of peripheral regeneration[edit]
Wallerian degeneration is a process that occurs before nerve regeneration and can be described as a cleaning or clearing process that essentially prepares the distal stump for reinnervation.[2] Schwann cells are glial cells in the peripheral nervous system that support neurons by forming myelin that encases nerves. During Wallerian degeneration Schwann cells and macrophages interact to remove debris, specifically myelin and the damaged axon, from the distal injury site.[2] Calcium has a role in the degeneration of the damage axon. Bands of Büngner are formed when uninnervated Schwann cells proliferate and the remaining connective tissue basement membrane forms endoneurial tubes. Bands of Büngner are important for guiding the regrowing axon.[5]
At the neuronal cell body, a process called chromatolysis occurs in which the nucleus migrates to the periphery of the cell body and the endoplasmic reticulum breaks up and disperses. Nerve damage causes the metabolic function of the cell to change from that of producing molecules for synaptic transmission to that of producing molecules for growth and repair. These factors include GAP-43, tubulin and actin. Chromatolysis is reversed when the cell is prepared for axon regeneration.[8]
Axon regeneration is characterized by the formation of a growth cone, which has the ability to produce a protease that digests any material or debris that remains in its path of regeneration toward the distal site. The growth cone responds to molecules produced by Schwann cells such as laminin and fibronectin.[5]
Neuron-intrinsic changes[edit]
Immediately following injury, neurons undergo a large number of transcriptional and proteomic changes which switch the cell from a mature, synaptically active neuron to a synaptically silent, growth state. This process is dependent on new transcription, as blocking the ability of cells to transcribe new mRNA severely impairs regeneration. A number of signaling pathways have been shown to be turned on by axon injury and help to enable long distance regeneration including BMP, TGFβ, and MAPKs. Similarly, a growing number of transcription factors also boost the regenerative capacity of peripheral neurons including ASCL1, ATF3, CREB1, HIF1α, JUN, KLF6, KLF7, MYC, SMAD1, SMAD2, SMAD3, SOX11, SRF, STAT3, TP53, and XBP1. Several of these can also boost the regenerative capacity of CNS neurons, making them potential therapeutic targets for treating spinal cord injury and stroke.[4]
Role of macrophages[edit]
The primary role of macrophages in peripheral regeneration is demylenation during Wallerian degeneration. Immunohistochemical analysis showed that in tellurium demylenated, crushed, and cut nerves, expression of lysozyme, which is a marker for myelin phagocytosis, and of ED1, which is a marker for macrophages, occurred in the same region. Lysozyme was also investigated with respect to the temporal progression of myelin phagocytosis by macrophages in nerve injury. Northern blotting showed that peak lysozyme mRNA expression occurred at an appropriate time with respect to temporal models of myelin phagocytosis. Macrophages do not phagocytose all cellular debris at the nerve injury site; they are selective and will salvage certain factors. Macrophages produce apolipoprotein E which is involved in rescuing cholesterol in damaged nerves. In the same investigation, temporal levels of apolipoprotein E mRNA expression in the three models for demylenation and nerve damage were consistent with respect to models for cholesterol salvage in nerve injury. Macrophages play a role in salvaging cholesterol during nerve injury.[12]
Macrophages also play a role in inducing the proliferation of Schwann cells that occurs during Wallerian degeneration. Supernatant has been collected from medium in which macrophages are active in myelin phagocytosis where lysosomal processing of the myelin occurs within the macrophage. The supernatant contains a mitogenic factor, a mitosis promoting factor, that is characterized heat and trypsin sensitivity, both of which characterize it as a peptide. Treatment of Schwann cells with the collected supernatant shows that it is a mitogenic factor and thus plays an important role in the proliferation of Schwann cells.[13]
Macrophages are also involved in the secretion factors that promote nerve regeneration. Macrophages secrete not only interleukin-1, a cytokine that induces expression of nerve growth factor (NGF) in Schwann cells but also an interleukin-1 receptor antagonist (IL-1ra). Expression of IL-1ra in mice with transected sciatic nerves via implantation of a tube releasing IL-1ra showed the regrowth of fewer myelinated and unmyelinated axons. Macrophage secretion of interleukin-1 is involved in stimulation of nerve regeneration.[14]
Role of neurite-promoting factors[edit]
Neurite promoting factors include many extracellular matrix proteins produced by Schwann cells at the distal stump including fibronectin and laminin. Fibronectin are components of the basal lamina and promote neurite growth and adhesion of the growth cone to the basal lamina. In regenerating neural cells, neurite promoting factors play a role in adhesion of the axon and include neural cell adhesion molecule (N-CAM) and N-cadherin.[20]
Prevention of nerve injuries[edit]
Methods to help prevent nerve injuries include injection pressure monitoring. The presence of a high opening injection pressure (> 20 PSI) is a sensitive sign of intrafascicular/intraneural needle tip placement. Extrafascicular needle tip placement is associated with low pressures (< 20 PSI). Also, high pressure injection was associated with neurologic deficits and severe axonal damage after the block. Other methods of preventing nerve injury include electrical nerve stimulation and ultrasonography. Electrical stimulation with a motor response at < 0.2 mA only can occur with an intraneural/intrafasciular needle tip location.[32]