Inflammatory Basis of Spinal Pain

CHAPTER 3 Inflammatory Basis of Spinal Pain



James D. Kang, Stephen Hanks



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.



Disc structure


The intervertebral disc is composed of four concentrically arranged layers including (1) the outer anulus fibrosus, (2) the fibrocartilaginous inner anulus fibrosus, (3) the transition zone between the anulus fibrosus and the nucleus pulposus, and (4) the nucleus pulposus. The outer anulus is composed of approximately ninety collagen sheaths bonded together in concentric laminated bands within which the fibers are arranged in the helicoid manner.


These sheaths are oriented at about 30° to the disc plane and at about 120° therefore in alternate bands. This orientation is important in resisting the high pressure of the nucleus, as well as maintaining stability against rotational forces. Cutting all fibers of the same orientation, while preserving fibers of the other direction, results in a greater increase in the axial rotation of the isolated motion segments than does removal of both facet joints. The inner anulus fibers attach directly to the cartilaginous endplate whereas the outer fibers attach directly to the vertebral body via Sharpey’s fibers.


The nucleus pulposus is centrally located and consists of a relatively random network of collagen and hydrated proteoglycans. The lumbar nucleus occupies 30–50% of the total disc area in cross-section. Water content varies from 70% to 90%, is highest at birth, and decreases with advances in age as the concentration of proteoglycans also decreases. The intervertebral disc is composed of a collection of macromolecules that include mostly collagen and proteoglycan. The matrix of the outer anulus consists of approximately 80% of type I collagens and small amounts of type V collagen. Inside the outer anulus, the concentrations of type II collagen and proteoglycan become progressively greater toward the center of the disc as the concentration of type I collagen decreases. Inside the nucleus, the concentration of type II collagen approaches 80% while type I is absent. Type II fibers are more hydrophilic than type I fibers and therefore are 25% more hydrated. Most of the data on the mechanical behavior of discs have been obtained from in vitro studies of spine specimens obtained at autopsy. There is evidence that the hydration in discs changes quickly after death, including transfer of water from the outer to inner anulus, and this may affect testing results in research using cadavers.


The presence of degenerative discs, as mentioned, is nearly universal as humans age. All disc tissue ages from birth to death, with the most marked changes occurring in the nucleus pulposus where the proteoglycan concentration, water content, and the number of viable cells all decrease. These changes are accompanied by fragmentation of the aggregating proteoglycans. Although all discs eventually show these same changes, the rate at which they show them varies not only from person to person, but within discs from the same individual.



Disc biomechanics


In general, tissue failure occurs because the loads to which they are exposed as stresses generated exceed the strength of the tissue. These can be tensile, compressive, or shear forces contributing to the damage. Stokes and Greenapple demonstrated strains of 6–10% during extremes of flexion and axial rotation in lumbar disc fibers.1 The strains were greater in the posterolateral areas than in the anterior regions. While pure axial compression, even in testing at very high loads, does not cause herniation of the nucleus pulposus, cyclic loading can cause annular tears that may eventually lead to disc herniation. Discs are known to exhibit creep, relaxation, and hysteresis. In these studies, the amount of hysteresis was shown to increase with load and decrease with age. These studies also demonstrate that nondegenerative discs creep less slowly than degenerative discs. This may indicate that there is less physiologic elasticity in degenerative discs.


Finite element analysis has effectively modeled the functional spinal unit (FSU). It has been shown that in compression the load is transferred from one vertebra to another through the endplates via the nucleus pulposus and the anulus fibrosus. The application of a load causes pressure to develop within the disc, pushing fibers out and away from the center of the disc. Rupture of the annular fibers was seen posterolaterally in the innermost layer during progressive failure analysis in compression and in shear loads at various rotations. The rupture progressed toward the periphery, with increased loads up to the maximum used in the analysis.


These structural changes to the disc and functional spinal unit can be readily seen with modern imaging techniques. However, mechanical phenomena or biomechanical changes are inadequate to explain some of the clinical observations made in the patients who have low back pain or radiculopathy. These include clinical improvement after treatment with powerful antiinflammatory medications, clinical improvement in the absence of a change in the pathologic anatomy of the disc, and the lack of correlation between symptoms or neurologic signs and the size of the disc herniation.



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











Erythema (rubor)
Warmth (calor)
Pain (dolor)
(Loss of function was added by Virchow)

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.



The process of inflammation


Inflammation is a complex, stereotypical reaction of the body in response to damage of cells in vascularized tissues. In avascular tissue such as the normal cornea or within the disc space, true inflammation does not occur. The cardinal signs of inflammation presented earlier, including redness, swelling, heat, pain and deranged function, have been known for thousands of years. The inflammatory response can be divided temporally into hyperacute, acute, subacute, and chronic inflammation. The response can be based on the degree of tissue damage, such as superficial or profound, or on the immunopathological mechanisms such as allergic, or inflammation mediated by cytotoxic antibodies, or inflammation mediated by immune complexes, or delayed-type hypersensitivity reactions. As presented earlier, the development of inflammatory reactions is controlled by cytokines, by products of the plasma enzyme systems (complement, the coagulation system, the kinin and fibrinolytic pathways), by lipid mediators (prostaglandins and leukotrienes) released from different cells, and by vasoactive mediators released from mast cells, basophils, and platelets. These inflammatory mediators controlling different types of reactions differ from one another. Fast-acting mediators such as the vasoactive amines and the products of the kinin system modulate the immediate response. Later, newly synthesized mediators such as leukotrienes are involved in the accumulation and activation of other cells. Once the leukocytes have arrived at the site of inflammation, they release mediators that control the later accumulation and activation of other cells. However, it is important to realize that in inflammatory reactions initiated by the immune system the ultimate control is exerted by the antigen itself, in the same way as it controls the immune response itself. For this reason, the cellular accumulation at the site of a chronic infection or in an autoimmune reaction is quite different from that at sites where the antigenic stimulus is rapidly cleared.


Inflammation can become chronic. In certain settings, the acute process, characterized by neutrophil infiltration and edema, gives way to a predominance of mononuclear phagocytes and lymphocytes. This probably occurs to some degree with the normal healing process that becomes exaggerated and chronic when there is an effective elimination of foreign material as in some infections, or introduction of foreign bodies, or deposition of crystals, or persistent inflammatory product secretions such as disc herniations.



Inflammatory cells



Mast cells and basophils


Mast cells and basophils play a central role in inflammation and immediate allergic reactions. They are able to release potent inflammatory mediators such as histamine, proteases, chemotactic factors, cytokines, and metabolites of arachidonic acid that act on the vasculature, smooth muscle, connective tissue, mucous glands, and inflammatory cells. Mast cells settle in the connective tissue and usually are not circulating in the bloodstream. Basophils are the smaller circulating granulocytes that settle into the tissues upon stimulation. Both these types of cells contain special cytoplasmic granules which store these mediators of inflammation. The release of these mediators is known as degranulation and can be induced by physical destruction such as mechanical trauma, or chemical substances such as proteases, or endogenous mediators including tissue proteases or cationic proteins derived from eosinophils and neutrophils, or immune mechanisms which may be IgE dependent or IgE independent. Neutral proteases, which account for the vast majority of the granule protein, serve as markers of mast cells and different types of mast cells. The newly generated mediators, often absent in resting mast cells, are typically produced during IgE-mediated activation and consist of arachidonic acid metabolites, principally leukotriene C4 (LPC4), and prostaglandin D2 (PGD2), and cytokines. Of particular interest in humans is the production of tumor necrosis factor (TNF-αγ, IL-4, IL-5, and IL-6). In the cytoplasm of both mastocytes and macrophages are special granules called lipid bodies where metabolism of arachidonic acid occurs and where their products, including leukotrienes, may be stored.



Eosinophils


Eosinophils are terminally differentiated end-stage leukocytes that reside predominantly in submucosal tissue and are recruited at the sites of specific immune reactions including allergic diseases. Like other granulocytes, they possess a polymorphous nucleus, although with only two lobes and no nucleus. The eosinophil cytoplasm contains large ellipsoid granules. Recently, it has been recognized that eosinophils are capable of elaborating cytokines that include those with potential growth factor activities and those with potential roles in acute and chronic inflammatory responses. Cytokines produced by human eosinophils that have activity in acute and chronic inflammatory responses include IL-1α, IL-6, IL-8, TNF-α, and both transforming growth factors TGF-α and TGF-β. In addition to the acute release of protein, cytokine, and lipid mediators of inflammation, eosinophils likely contribute to chronic inflammation including the development of fibrosis. Additional roles for the eosinophil modulating extracellular matrix deposition and remodeling are suggested by studies of normal wound healing. During dermal wound healing, eosinophils infiltrate into the wound site and sequentially express TGF-α early and TGF-β later during wound healing.



Neutrophils


Neutrophils, also known as polymorphonuclear leukocytes, represent 50–60% of the total circulating leukocytes and constitute the first line of defense. Once an inflammatory response is initiated, neutrophils are the first cells to be recruited. Neutrophils contain granules which contain antimicrobial or cytotoxic substances, neutral proteinases, acid hydrolases, and a pool of cytoplasmic membrane receptors. The granules contain, in addition to other substances, serine proteases such as elastase and cathepsin-G, which hydrolyze protein in cell envelopes. Substrates of granulocyte elastase include collagen crosslinks and proteoglycans, as well as elastin components of blood vessels, ligaments, and cartilage. Cathepsin-G cleaves cartilage proteoglycans while granulocyte collagenases are active against type I, and to a lesser degree type III collagen from bone, cartilage, and tendon. Collagen breakdown products have chemotactic activity for neutrophils, monocytes, and fibroblasts. Although neutrophils are essential to host defense, they have also been implicated in the pathology of many chronic inflammatory conditions and ischemia–reperfusion injury. This may be triggered by substances released from damaged host cells or as a consequence of superoxide generation through xanthine oxidase.


Neutrophils, macrophages, endothelial, and other cells produce two types of free radicals. The first type is represented by reactive oxygen intermediates that are formed in neutrophils by the activity of NADPH oxidase. The second type includes reactive nitrogen intermediates such as nitric oxide. Reactive nitrogen intermediates have been of some interest in low back-associated pain. These are sometimes called reactive oxynitrogen intermediates. The pathway by which they are originated is an oxidative process in which short-lived nitric oxide is derived from the guanidino nitrogen in the conversion of L-arginine to L-citrulline. This reaction is catalyzed by nitric oxide synthase (NOS) and, like the respiratory burst, it involves oxygen uptake. Three distinct isoforms of nitric oxide synthase representing three distinct gene products have been isolated and purified. The three isoforms vary considerably in their subcellular location, structure, kinetics, regulation, and hence functional roles. Two of the enzymes are constantly present and termed constitutive NOS (cNOS). The endothelial cNOS is mostly membrane bound and formed only in endothelial cells. The neuronal cNOS was identified in cytosol or central and peripheral neurons. The third isoform is an inducible form that is not present in resting cells. Cytokines are a potent stimulus for iNOS production or suppression. Those with an apparent stimulating effect include IFN-γ, IL-1, IL-6, TGF-α, GM-CSF, and PAF (platelet activating factor) while suppression has been observed by IL-4, IL-8, IL-10, TGF-β, PDGF (platelet derived growth factor), and MDF (macrophage deactivating factor). Cytokines are basic regulators of all neutrophil functions. Many of them, including somatesthetic growth factors and pyogens, have shown to be potent neutrophil priming agents. Neutrophils are also capable of de novo synthesis and secretion of small amounts of some cytokines including IL-1, IL-6, IL-8, TNF-α and GM-CSF.


Bioactive lipids originate mainly from arachidonic acid which is an abundant constituent of neutrophil membranes. Arachidonic acid is metabolized to prostaglandins, leukotrienes, and lipoxins. LTB4 is a strong neutrophil chemoattractant that may play a role in the priming process. Vasoactive leukotrienes LTC4, LTB4, and LTE4 increase microvascular permeability and may contribute to ischemia–reperfusion injury. In contrast to leukotrienes, prostaglandins suppress most neutrophil functions, possibly through their ability to elevate intracellular cyclic AMP.

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Sep 8, 2016 | Posted by in PHYSICAL MEDICINE & REHABILITATION | Comments Off on Inflammatory Basis of Spinal Pain

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