INTRODUCTION

Low back pain with or without radiculopathy continues to be a significant clinical entity causing major disability in patients. However, the etiology of low back pain and the exact pathophysiology remains elusive. Intervertebral disc degeneration has been implicated as one of the key factors associated with low back pain. The intervertebral disc continues to be a structure of great interest because its degeneration or failure may influence a variety of structures in processes believed to play a role in low back pain. There has been a large body of recent work focusing on the interaction between biomechanics and the biochemistry of disc degeneration and their seemingly coupled interaction.

Low back pain is undoubtedly one of the largest health problems affecting society, both individually and as a whole. It is the second most common reason listed for a doctor’s office visit and the lifetime prevalence is estimated at 91%. Of the total Workmen’s Compensation expenditure nationwide, it accounts for somewhere between 70% and 90%. It is the second leading cause of disability worldwide and its incidence is increasing disproportionately to the population growth and other disabling conditions.

For these important reasons, characterizing the underlying causes of low back pain has become more important in the scientific literature in the last 7–10 years.

THE INTERVERTEBRAL DISC

The intervertebral disc has many functions including stabilization of the spine by attaching vertebral bodies together and allowing movement between these bodies giving the spine its flexibility. With the facet joints, the spine bears the entire compressive load to which the trunk of the body is exposed. Discs within the lumbar spine are exposed to three times or more the weight of the trunk while in the sitting position and this number can double during certain activities such as jumping, lifting out of position, or trauma. Changes within the disc as humans age affects the ability of the spine to respond to the loads to which it is subjected.

INFLAMMATION

Acute inflammation is a response of living tissue to damage and it has three functions. The inflammatory exudates formed carry protein and fluid in cells from blood vessels to the damaged area to mediate local defenses. It also helps eliminate any infective agent that is present in the area, and helps break down damaged tissue, facilitating its removal from the site of the damage. Acute inflammation may result from physical damage, chemical substances, microorganisms, or other agents. The response results in changes in local blood flow and increased permeability of blood vessels that facilitates the escape of proinflammatory cells from the blood into the tissues. These changes are essentially the same whatever the cause and wherever the site. Usually, acute inflammation is a short-lasting process. However, the length of the process is probably dependent on the inciting cause.

Hypersensitivity reactions are another cause of acute inflammation, as are physical agents such as tissue damage from trauma, ultraviolet or ionizing radiation, burns, or frostbite. Irritants and corrosive chemicals can cause inflammation and tissue necrosis. Lack of oxygen or necrosis is another mechanism by which acute inflammation can propagate. In this particular cause, the reduction of oxygen and nutrients resulting from inadequate blood flow or infarction is a potent inflammatory stimulus.

Celsus described the four principal effects of acute inflammation nearly 2000 years ago (Table 3.1). These include redness from acute dilatation of small blood vessels within the area. Heat, or warmth, is usually seen only in the peripheral parts of the body such as the skin. It is also due to the increased blood flow or hyperemia through the region from vascular dilatation. Swelling results from edema which is the accumulation of fluid in the extravascular space and from the physical mass of the inflammatory cells migrating to the area. Pain is one of the best-known features of acute inflammation and it results partly from the stretching and distortion of tissues due to the edema in the area. Chemical mediators of acute inflammation including bradykinin, the prostaglandins, and serotonin are also known to induce pain. Loss of function is a well-known consequence of inflammation added by Virchow to the list originated by Celsus. Movement of an inflamed area is consciously and reflexively inhibited by pain, while severe swelling or local muscle spasm may limit movement of the area.

Table 3.1 Celsus’s original description of the characteristic signs of inflammation

The acute inflammatory response involves three changes or processes. Changes in the vessel size and flow, increased vascular permeability and the formation of the fluid exudate, and migration or de-margination of polymorphonuclear leukocytes (PML) into the extravascular space are characteristic processes of acute inflammation. Briefly, these early stages involve small blood vessels adjacent to the area of the tissue damage, which become dilated with increased blood flow. As blood flow begins to slow, the endothelial cells swell and partially retract so that they form a leaky continuum within the blood vessel. The vessels become leaky, which permits the passage of water, salts, and small proteins into the damaged area. One of the main proteins to leak out during this period is fibrinogen. Circulating PMLs initially adhere to the swollen endothelial cells and then migrate through these channels created by the retracted endothelial cells and through the basement membrane, passing into the area of tissue damage. Later on, blood monocytes (macrophages) migrate in a similar way. The microcirculation consists of a network of small capillaries that lie between the arterioles. These microcapillaries initially experience an increased blood flow following the initial phase of arteriolar constriction, which is transient. Blood flow to the injured area may increase up to tenfold during this time, but then blood flow begins to slow down, allowing the leukocytes to de-marginate into the area. The slowing of this blood flow, which follows the phase of hyperemia, is due to increased vascular permeability and allows plasma to escape into the tissues while blood cells stay within the blood vessels. Blood viscosity is therefore relatively increased as the percentage of red cells relative to white cells and other proteins increases. The increased vascular permeability increases capillary hydrostatic pressure as well as allowing the escape of plasma proteins in the extravascular space. Instead of the usual return of fluid into the vascular space, however, proteins act to increase the colloid osmotic pressure in the extravascular space. Consequently, more fluid leaves the vessel than comes back and the net escape of protein rich fluid is called exudation.

Experimental work has demonstrated three patterns of increased vascular permeability. There is an immediate response that is transient, lasting 30–60 minutes, mediated by histamine acting on the endothelium directly. A delayed response starts 2–3 hours after injury and may last for up to 8 hours. This is mediated by factors synthesized by local cells such as bradykinin or factors from the complement cascade, or those released from dead neutrophils in the exudate. A third response that can be prolonged for more than 24 hours is seen if there is a direct necrosis of the endothelium. In the later stages of acute inflammation where movement of neutrophils becomes important, experimental evidence has shown purposeful migration of neutrophils along a concentration gradient. This movement appears to be mediated by substances known as chemotactic factors diffusing from the area of damage. The main neutrophil chemotactic factors are C5a, LTB4, and bacterial components. These factors, when bound to the receptor on the surface of a neutrophil, activate secondary messenger systems stimulating increased cytosolic calcium with the assembly of cytoskeletal specializations that are involved in their ability to move.

The spread of the inflammatory response following injury to a small area of tissue suggests that chemical substances are released from the injured tissues spreading out to uninjured areas. These chemicals are called endogenous mediators and contribute to the vasodilatation, de-margination of neutrophils, chemotaxis, and increased vascular permeability. Chemical mediators released from the cells include histamine, which is probably the best-known chemical mediator in acute inflammation. It causes vascular dilatation in the immediate transient phase of increased vascular permeability. This substance is stored in mast cells, basophils and eosinophils, as well as platelets. Histamine released from those sites is stimulated by complement components C3a and C5a, and by lysosomal proteins released from neutrophils. Lysosomal compounds are released from neutrophils and include cationic proteins that may increase vascular permeability and neutral proteases, which may activate complement. Prostaglandins are a group of long-chain fatty acids derived from arachidonic acid and synthesized by many cell types. Some prostaglandins potentiate the increase in vascular permeability caused by other compounds. Part of the antiinflammatory activity of drugs such as aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) is attributable to inhibition of one of the enzymes involved in prostaglandin synthesis. Leukotrienes are also synthesized from arachidonic acid, especially in neutrophils, and appear to have vasoactive properties. SRS-A (slow-reacting substance of anaphylaxis) involved in type I hypersensitivity is a mixture of leukotrienes. Serotonin (5-hydroxytryptamine) is present in high concentration in mast cells and platelets and is a potent vasoconstrictor. Lymphokines are a family of chemical messengers released by lymphocytes. Aside from their major role in type IV sensitivity, lymphokines also have vasoactive or chemotactic properties.

Within the plasma are four enzymatic cascade systems including the complement system, the kinins, the coagulation factors, and the fibrinolytic system, which are interrelated and produce various inflammatory mediators. The complement system is a cascade system of enzymatic proteins and can be activated during the acute inflammatory reaction in various ways. In tissue necrosis, enzymes capable of activating complement are released from dying cells. During infection, the formation of antigen–antibody complexes can activate complement via the classical pathway, while endotoxins of Gram-negative bacteria activate complement via the alternative pathway. Products of the kinin, coagulation, and fibrinolytic systems can also activate complement. The products of complement activation that are most important in acute inflammation include C5a, which is chemotactic for neutrophils, increases vascular permeability, and releases histamine from mast cells. C3a has similar properties to those of C5a, but is less active. C5, 6, and 7 are all chemotactic for neutrophils and, in combination with 8 and 9, have additional cytolytic activity. Finally, C4b, C2a, and C3b are all important in the opsonization of bacteria, which facilitates phagocytosis by macrophages.

The kinin system includes the kinins, which are peptides of 9 to 11 amino acids that are important in increasing vascular permeability. The most important of these is bradykinin. The kinin system is activated by coagulation factor XII. Bradykinin is also an important chemical mediator of pain, which is a cardinal feature of acute inflammation.

Within the coagulation system, factor XII, once it has been activated by contact with extracellular materials, will activate the coagulation, kinin, and fibrinolytic systems directly. This system is responsible for the conversion of soluble fibrinogen into fibrin, which is the major component of the acute inflammatory exudate. These fibrin degradation products result from the lysis of fibrin in the presence of plasmin.

Within the fibrinolytic system, the fibrin degradation products have effects on local vascular permeability.

The PML is the characteristic cell in acute inflammation. Its ability to move in a response to a concentration gradient of chemotactic factors has been well demonstrated and is mediated by cytosolic calcium. Neutrophils are able to bind to bacterial components via their Fc receptor and are able to phagocytose various particles or organisms and partially liquefy them with toxic compounds contained within lysosomes.

Following tissue damage or loss from any cause, including damage due to the inflammatory process, there may be resolution, regeneration, or repair. All of these processes may occur in the same tissue or begin as soon as there is significant tissue damage. Healing does not wait for inflammation or other mechanisms to subside, but usually takes place concurrently. The outcome depends on which of these three processes predominate and on a number of factors. Resolution tends to occur when there is little tissue destruction as well as a limited period of inflammation and short, successful treatment. Regeneration occurs when lost tissue is replaced by a proliferation of cells of the same type reconstructing the normal architecture. Regeneration proceeds based on cell type, and cells are usually classified into three groups based on their ability to regenerate. Labile cells are those that are normally associated with high rate of loss and replacement and therefore have a high capacity for regeneration. Stable cells do not normally proliferate to a significant extent but can be stimulated to do so after they have been damaged. Permanent cells are unable to divide after their initial development and therefore cannot regenerate when lost (i.e. neurons).

Tissue architecture is also important. Simple structures are easier to reconstruct following damage than complex ones. An imperfect attempt at regeneration can have important clinical consequences such as the cirrhosis that results after damage to the liver and the resulting abnormal nodular architecture from the repair. This process is also dependent on the amount of tissue loss. There must be cells left in the area to regenerate, as well as a reasonable volume to regenerate prior to scar formation. In repair, the process results in formation of a fibrous scar from the granulation tissue. Following the acute inflammation and phagocytosis of necrotic debris and other foreign material, blood vessels proliferate and fibroblasts assemble at the edge of the damaged area. As the endothelial cells and fibroblasts grow into the damaged area, vascularization also proceeds. Fibroblasts continue to proliferate, producing collagen and giving the tissue mechanical strength; eventually a scar consisting of dense collagen results. Factors influencing healing include the rate of healing, the presence of foreign material or of continuing inflammation, inadequate blood supply, abnormal motion, or certain medications that inhibit this process. Systemically, the healing process becomes less effective and slower with increasing age. Nutritional deficiencies play an important role as well as metabolic diseases such as renal failure or diabetes mellitus. Some patients with ongoing malignancies are actually in a catabolic state and unable to heal even simple wounds. Additionally, corticosteroids are important systemic inhibitors of wound healing.