Учебники / Otolaryngology - Basic Science and Clinical Review

that establish a mixture of fibrous tissue, composed of cartilage and loosely woven bone known as a soft callus. The callus forms a fibrous union surrounding the break and entering the marrow cavity. Type II collagen composes 50% or more of this callus.With formation of the soft callus, the fracture begins to stabilize, and inflammation ends. Movement at the site, bacterial contamination and infection, soft tissue injury around the site, insufficient vascularity, and malalignment can cause failure of soft callus formation.

Hard bone forms in the third stage, as the cartilaginous portion of the soft callus is replaced by endochondral ossification beginning 3 to 4 weeks after injury.Type II collagen is degraded and replaced by type I.The organic matrix calcifies as calcium hydroxyapatite is deposited and the developing calcified matrix is interconnected by brisk neoangiogenesis.The new blood vessels permit entry of osteoprogenitor cells that then mature into osteoclasts. The hard callus is visible radiographically as an excess of calcified bone in and around the fracture site. The concave surface is electronegative and forms more osteoblasts, while the electropositive charge of the convex surface is populated by more osteoclasts. The presence of electric charges on the convex and concave surfaces of the callus can be influenced at this stage by externally applied electrical stimulation, a technique that may be used to promote healing, especially when delayed union or nonunion is suspected.

The final stage of bone healing, reshaping, involves remodeling and modeling. Remodeling involves the cell-mediated breakdown and reformation of bone, and modeling normalizes the bony macrostructure, providing an orientation reflecting the lines of bone stress. Wolff’s law refers to the ability of bone to reorient its microstructure along the lines of biomechanical stress. As these processes occur, continuing over years, radiological evidence of the fracture nearly disappears.

Bone healing in membranous bone differs from that of endochondral bone because healing can proceed without the intermediate stages of soft and hard callus formation.This is called primary bone healing. New bone bridges the fracture site early, with type I collagen predominating.Within 6 weeks of injury new osteons, with well-formed lamellae and haversian canals, are present, providing a regeneration of the bone at the fracture site. Facial fractures need to be reduced and stabilized soon after injury, not only to minimize pain and restore appearance and function, but also because strength in the fracture site may make the reduction impossible within 2 weeks. This type of primary healing in endochondral bone may occur with minimal tissue damage and immediate rigid fixation of the fracture.

BONE GRAFTS

Bone grafts transplanted into the site generate new bone formation through three processes: (1) the presence of living cells, (2) invasion of the site by native osteoblasts, and

(3) the transformation of host cells into osteoblasts. Bone grafts may be autologous, cadaver donor, or an artificial calcified matrix. Coral has been used successfully as a bone substitute. Autologous bone is always preferable. For significant bony defects, microvascular osseous-free flaps can provide the best functional result with the most bone.

The surgeon can best avoid the pitfalls of nonunion, malunion, and fibrous union and enhance the process of facial bone wound healing by relying on three basic principles: (1) creating optimum bone to bone contact (reduction), (2) rigid fixation, and (3) immobilization for an adequate period to allow healing. Rigid fixation with plates and screws, with or without bone grafts for large defects, provides a treatment that adequately addresses all three principles.

TYMPANIC MEMBRANE

The tympanic membrane (TM) possesses a powerful ability to repair itself due to the unusual features of its epithelial structure and migratory capacities. It is composed of three histological layers.The outer layer consists of keratinizing stratum corneum.The middle section is a thin layer of connective tissue.The innermost layer consists of a mucosal layer of cuboidal surface epithelium. The concept of epithelial generation entails the migration of epithelium around theTM in a centripetal fashion from anterior to posterior, then laterally along the canal wall.The TM heals in a process similar to the cutaneous process described previously. It differs from skin with respect to wound healing during the proliferative phase. In the skin, the fibrous connective tissue layer precedes the migration of the epithelium across the wound. Conversely, in the TM, the epidermal layer plays the critical initial role in migration, whereas the fibrous layer is usually the last layer to cross the defect and in many cases does not, resulting in a dimeric membrane, commonly referred to by the misnomer “monomer.”

The majority of traumatic TM perforations will heal spontaneously without intervention. Several factors inhibit or delay closure of the TM, resulting in a chronic perforation. A chronic perforation is caused by the growth of squamous epithelium over the edges of a perforation to meet the mucosal layer. This epithelialized wound edge forms a fistula between the middle ear and the canal. Chronic perforation can occur due to severe acute infection, chronic infection, large defects secondary to trauma, presence of a burn, concurrent

steroid administration, old age, and poor nutritional status.

FETAL HEALING

The key to solving the problem of scar formation lies in an increased understanding of fetal healing.Although the field is in its infancy, successful treatment of such lethal and near-lethal defects as hydronephrosis, hydrocephalus, lung hypoplasia, diaphragmatic hernia, myelomeningocele, sacrococcygeal teratoma, laryngeal atresia, and stenosis is now possible and becoming more frequently performed and widely available. Risks to the mother and fetus still limit fetal surgery for conditions such as cleft lip and palate, but they will certainly be one of the next applications.

Specific aspects of fetal healing believed to contribute to the scarless regeneration that has been observed include faster cell proliferation, lower oxygen tension, the presence of a fluid environment (amniotic fluid), sterile conditions, decreased inflammatory response, a faster and more organized matrix deposition, and lower concentrations of growth factors TGF- , bFGF, higher levels of insulin-like growth factor and hyaluronic acid stimulating factor, and reduced levels of neoangiogenesis following injury. In general, studies indicate that it is the fetal cells themselves that provide the result, rather than the environment. As gestation progresses, regeneration capacity decreases, and scarless healing ends during the second trimester. This correlates with an increasing inflammatory response to injury.

The fetus does have the capacity to form scar tissue at an early age, with intestinal adhesions found following intrauterine diaphragmatic hernia repair, while at the same time, the thoracic incision heals with no scar. Organ differences in healing, age-related differences, and the variety of distinctive biochemical and cellular activities that characterize fetal healing bring new insights into tissue repair and regeneration and provide tantalizing insight into all healing, but they have not provided the key to successfully reducing scar formation after birth.

PERIOPERATIVE PREPARATION FOR SUCCESSFUL WOUND HEALING

The surgical outcome is predicated on the skill of the surgeons and anesthesiologists, the nature of the disease being treated, and the condition of the patient. Careful attention to preparation for surgery will optimize the likelihood of a satisfactory result. Pretreatment of systemic conditions will significantly reduce the incidence of postoperative

complications, especially wound healing problems and infections. Conditions including hypertension, malnutrition, pulmonary insufficiency, diabetes mellitus, hypothyroidism, smoking cessation, and existing skin, sinus, or urinary tract infections should be treated.Treatment with vitamins A and C in those patients on chronic steroids should be initiated before surgery. Assuring adequate blood volume, maintaining body temperature (avoid a cold operating room at the time of induction) to minimize thermoregulatory vasoconstriction, and treating pain and anxiety will facilitate tolerance of anesthesia and reduce complications.

During surgical procedures attention should focus not just on the procedure but also on several other aspects of patient management.These include maintaining antibiotic levels (if necessary) and body temperature, keeping all tissues in the surgical field moist, avoiding undo pressure on any parts in the surgical field or on the patient on the table, irrigating the wound with antibiotic solutions if contamination has occurred, using cautery with care to avoid leaving charred or necrotic tissue in the wound, and considering a delayed wound closure if the field is heavily contaminated. Discussions with the anesthesiologist should assure that fluid replacement keeps abreast of fluid losses, that systemic mean arterial blood pressure remains stable, and that urine output is adequate.

Postoperative attention to details, such as keeping the patient warm and pain free, optimizing oxygen delivery, maintaining antibiotic levels, instituting nutrition quickly, using parenteral or enteral nutritional supplements if needed, and continuing treatment of coexisting conditions like hypertension and diabetes, will all improve the quality of outcome from the surgical treatment.

SUGGESTED READINGS

Achaur, BM, Erickson E. Principles and techniques. In: Plastic Surgery: Indications, Operations and Outcomes. St. Louis: Mosby; 2000 Granick MS, Long CD, Ramasastry SS.Wound healing state of the

art. Clinics Plas Surg 1998;25:3

Hom DB, Szachowicz.Wound healing for the otolaryngology’s–head and neck surgeon. Otolaryngol Clin NA 1995;28(10):5

Hunt TK. The role of the macrophage in wound healing. Surg Forum 1976;27(62):16–18

Manjo G.The Healing Hand: Man andWound in the AncientWorld. Cambridge, MA: Harvard University Press; 1975

Niinikoshi JH. Clinical hyperbaric oxygen therapy: wound perfusion and transcutaneous oximetry.World J Surg 2004;28(3):307–311 Wattel F, Matthieu D, Coget JM, et al. Hyperbaric oxygen in the management of chronic vascular wounds. Angiology 1990;

41(1):59–65

Witte MB, Barbul A. General principles of wound healing. Surg Clin North Am 1997 June; 77(3):509–528

SELF-TEST QUESTIONS

For each question select the correct answer for the lettered alternatives that follow.To check your answers, see Answers to Self-Tests on page 715.

1.Wound healing is initiated by cellular and biochemical reactions. Critical events involved in the normal wound healing process include all but one of the following:

A.The extrinsic pathway is initiated by tissue factor, binding to factors VII and VIIa. Factor XIII (fibrin-stabilizing factor) initiates fibrin clot development.

B.The intrinsic coagulation path is activated via factor XII, when blood is exposed to foreign surfaces.

C.Thrombin clot within the wound provides the provisional matrix for the extracellular matrix (ECM) that becomes the scaffolding for subsequent cellular migration, adhesion, and proliferation.

2.The first cell type that migrates into the wound following injury is

A.Macrophage

B.Platelet

C.Neutrophil

D.Fibroblast

3.The cell responsible for the production of glycosaminoglycans, hyaluronic acid, chondroitin-4 sulfate, dermatan sulfate, and heparin sulfate substrates for ground substance is

A.Neutrophil

B.Macrophage

C.Platelet

D.Fibroblast

4.Incisions made parallel to the relaxed lines of skin tension will

A.Most likely form keloids

B.Widen significantly in contrast to those made at a right angle

C.Never hypertrophy

D.Result in satisfactory healing

Allergic diseases (allergic rhinitis, asthma, urticaria, and atopic dermatitis) are very common, affecting 20 to 25% of the U.S. population. They are the sixth leading cause of chronic disease in the United States, with a cost of more than $10 billion each year.

A 1993 survey revealed that allergic rhinitis alone affects 39.9 million persons in the United States. This

results in 811,000 missed workdays, 824,000 missed school days, and 4,230,000 reduced activity days.A high prevalence of allergic rhinitis has also been reported in England,Australia, and Sweden.

This chapter will discuss current understanding of the pathophysiology, diagnostic approaches, and therapy of allergic diseases, with an emphasis on allergic rhinitis.

Figure 3–1 Allergic sensitization and degranulation. The process of sensitization and degranulation in mast cells is analogous to the detonation of a bomb. Initial binding of specific IgE to the naive mast cell surface “primes” the cell for activity. Subsequent binding of allergen to the mast cell is akin to lighting the fuse of

the bomb. Intracellular biochemical events lead to the ultimate “explosion,” a cellular degranulation leading to mediator release. (From Allergic Diseases: Diagnosis and Treatment, edited by Phil Lieberman and John A.Anderson, Humana Press,Totowa, New Jersey, 1997. Reprinted with permission.)

PATHOPHYSIOLOGY OF

ALLERGIC DISEASES

The tendency to develop allergy is inherited and is termed atopy.The process by which one initially becomes allergic to a substance begins with sensitization, which is a two-step process (Fig. 3–1). During the initial stage of sensitization, the allergen is processed by anti- gen-presenting cells (macrophages, dendritic cells) and presented to T lymphocytes.T lymphocyte–derived interleukins (ILs), especially IL-4 and IL-13, induce immunoglobulin E (IgE) production by B cells and plasma cells in the presence of the allergen.This newly formed IgE adheres to tissue mast cells or to circulating blood basophils.This process rarely produces any symptoms.

The second step in this process involves the reexposure of a sensitized individual to the allergen. Cross-linking of at least two adjacent IgE molecules by the allergen induces mast cell/basophil release of histamine and other proinflammatory mediators within minutes.These mediators cause the typical allergic symptoms, which may range from mild (itching, sneezing) to severe (anaphylaxis), resulting in death.

This immediate reaction to an allergen (the early-phase reaction) cannot fully explain allergic symptoms, which may last for hours to days. This mechanism also cannot

explain the therapeutic efficacy of corticosteroids, which lack the ability to inhibit immediate responses to an allergen. A large body of research indicates that the immediate allergic reaction is usually followed 2 to 8 hours later by a late-phase reaction, which produces the chronic or prolonged symptoms. This reaction can develop in the nose, respiratory tract, skin, and other anatomical locations, and is marked by infiltration of many types of cells, primarily eosinophils, but also basophils, mononuclear cells, and neutrophils. All these cells contribute to the late-phase reaction by producing additional proinflammatory mediators and cytokines.

CELLULAR COMPONENTS OF THE ALLERGIC RESPONSE

MAST CELLS AND BASOPHILS

The major effector cells of allergic reaction are mast cells and basophils. Both cell types are derived from hemopoietic progenitor cells in the bone marrow and are the major source of histamine and other allergic mediators. Morphologically, human basophils have a segmented nucleus with marked condensation of nuclear chromatin and contain round or oval cytoplasmic granules.

In contrast, mast cells typically appear as either round or elongated cells with a nonsegmented nucleus.

Basophils mature in the bone marrow and then circulate in the blood. Mast cells, however, leave the circulation and mature and reside predominantly in connective tissues. There are two types of mast cells in humans: mast cells containing the enzyme tryptase (MCTs) and mast cells containing both tryptase and other enzymes, including chymase, mast cell carboxypeptidase, and cathepsin G (MCTCs). MCTs reside mainly in the lungs and intestinal mucosa, and MCTCs in the skin and intestinal submucosa. It is thought that cytokine differences in the microenvironment of the tissues are responsible for this cellular differentiation. Precursor cell differentiation to MCT (mucosal) mast cells is the result of mature cytokines such as stem cell factor (SCF). It is not clear what causes a mast cell to develop as either a MCT (mucosal mast cell) or MCTC (connective tissue mast cell). However, in vitro studies suggest that T lymphocycte associated activity appears to be important in the development of MCT cells, whereas SCF and other fibroblast cytokines. Fibroblast cytokines are important in the development of both types of mast cells.

In addition to containing mediator-rich granules, the most important distinguishing feature of mast cells and basophils is their ability to tightly bind the allergy-inducing antibody IgE. Mast cells and basophils both possess a high-affinity receptor for IgE, Fc(RI), and are the principal cells in the body with these receptors. Once bound to Fc(RI), IgE can remain on the cell surface for many months. Other cells, such as B cells and activated T cells, possess a low-affinity IgE receptor, Fc(RII), which has been identified as the CD 23 molecule. However, the exact role of this low-affinity IgE receptor in allergy is not known.

The most important cellular event that underlies expression of basophil or mast cell function is degranulation, which occurs by cross-linking of Fc(RI) receptors. Bridging of these receptors through bound IgE molecules on the mast cell or basophil causes several intracellular biochemical events catalyzed by phospholipase C and phospholipase A2. These events culminate in mast cell/ basophil degranulation and activation, with release of various stored or newly formed mediators such as histamine, leukotrienes, and prostaglandin D2. Monovalent antigens will not trigger mast cell or basophil activation.

In addition to IgE and specific antigen, a variety of substances can directly elicit release of mediators from mast cells and basophils.A few examples of these include physical stimuli such as cold, exercise, and sunlight; drugs such as vancomycin and opiates; and chemical compounds such as radiological contrast dyes.

EOSINOPHILS

Eosinophils play a major role in chronic allergic reactions as effector cells. They are derived from bone marrow and are similar in size to neutrophils but have bilobed nuclei and distinctive cytoplasmic granules.They are most abundant in tissues that have a mucosal epithelial interface with the environment, such as the respiratory and gastrointestinal tracts. The major mediators stored in eosinophil cytoplasmic granules include major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, lysosomal hydrolase, and lysophospholipase.The latter enzyme forms the CharcotLeyden crystals that are found in the sputum of asthmatics and which are evidence of prior eosinophil degranulation.

The development of eosinophils is promoted by at least three cytokines. Granulocyte-macrophage colony– stimulating factor (GM-CSF), IL-3, and IL-5, have the most cell-specific effects on eosinophil differentiation and production. IL-5 also rapidly increases eosinophil release from the bone marrow into the circulation.

Human eosinophils express receptors for IgG, IgA, and IgE. Receptors for complement components and several cytokines have also been found on eosinophils. Though the exact protective function of eosinophils is still unclear, they are thought to play an important role in defense against the helminthic parasites.

Eosinophils are major contributors to the pathophysiology of many allergic disorders, including allergic rhinitis. Many studies have demonstrated the influx of eosinophils during late-phase allergic reactions. For instance, there is a significant increase in the total number of eosinophils and the number of activated eosinophils in the epithelium and lamina propria in the nasal biopsy specimens of patients with grass pollen allergy after an experimental, out-of-season, 2-week allergen exposure. However, the majority of studies have failed to document a correlation between symptom scores, pollen counts, released mediators, and the total number of eosinophils or number of activated eosinophils, which suggests that other cells in the nasal mucosa along with their mediators are also involved in producing allergic symptoms.

T LYMPHOCYTES

T lymphocytes are important regulators of allergic reactions. As described previously, they are essential for the production of IgE and for the production of cytokines that activate and differentiate mast cells and eosinophils. During ontogeny in the thymus,T cells eventually develop into either CD4 or CD8 cells. CD4 cells, which represent approximately two thirds of peripheral blood

T lymphocytes, recognize antigens bound to class II human leukocyte antigen (HLA) molecules. CD8 lymphocytes, which represent approximately one third of peripheral blood T cells, recognize antigens bound to class I HLA molecules.

CD4 T lymphocytes are often associated with helper function, and CD8 cells are believed to have suppressor and cytotoxic properties, although these correlations are not absolute.

Five to 10% of peripheral blood lymphocytes are CD4–CD8. It is thought that they may play a role in the recognition of glycolipids.

Helper T lymphocytes are divided into Th1 and Th2 cells based on their cytokine production patterns.Th2 cells primarily produce IL-4, IL-5, IL-9, IL-10, and IL-13. They play an important role in the pathogenesis and promotion of allergic diseases and humoral immunity. IL-4 induces the differentiation of Th2 cells from naive T helper cells (To) and inhibits the differentiation of Th1 lymphocytes.

Th1 cells, in contrast, act primarily to suppress allergic mechanisms and reactions.They induce and promote cellmediated inflammation by secreting IL-2, tumor necrosis factor (TNF- ), and interferon . The latter cytokine has an inhibitory effect on the differentiation of Th2 cells and IgE production. IL-12 from macrophages promotes the differentiation ofTh1 cells from theTo population.

The discovery of the Th1 and Th2 cells has led to an interesting explanation of increasing prevalence of allergic diseases in Western countries. According to this theory, exposure to infections early in life tends to favor Th1 immune responses and suppresses Th2 responses. Improved immunization, better control of infectious diseases, and widespread use of antibiotics in Western countries may encourage Th2 responses and leads to a higher prevalence of allergic diseases.A recent observation that children who responded well to bacille CalmetteGuérin (BCG) vaccination were less likely to develop IgE response later in life supports this view. Conversely, there is a decreased prevalence of allergy and asthma in younger siblings presumably because they are exposed to more childhood infections at an earlier age.

B LYMPHOCYTES

The major contribution of B lymphocytes to allergic reactions is through their production of IgE. B cells mature in the bone marrow and differentiate into plasma cells, which are responsible for most of the immunoglobulin production in the body, including IgE. This production is primarilyT cell mediated.Thus activation ofTh2 cells with IL-4 elaboration induces a B cell switch from IgM produc-

tion to IgE and IgG4 production, and transforming growth factor (TGF- ) in combination with IL-10 induces a switch from IgM production to IgA1 and IgA2 production.

Most IgE-producing B cells and plasma cells are located in tissues where allergic reactions occur, and most IgE is produced locally. This is in contrast to the majority of the other immunoglobulins, which are produced in secondary lymphoid organs, the spleen and lymph nodes.

ALLERGIC ANTIBODIES

Immunoglobulin E plays a central role in allergic disease. The ability to produce large amounts of this antibody distinguishes atopic from nonatopic individuals because the latter individuals usually produce other classes of antibodies (IgG, IgM) when exposed to an antigen. Studies have shown that total serum IgE concentrations tend to be higher in allergic adults and children compared with nonallergic individuals, but the diagnostic value of this test is limited.

The production of IgE is mainly under the control of two cytokines, IL-4 and IL-13, which are produced by Th2 cells. Indeed, IL-4 is such a necessary signal for IgE production that mice genetically engineered to be devoid of IL-4 (IL-4 knockout mice) are unable to synthesize IgE. Although several studies have demonstrated that only IL-4 and IL-13 are capable of inducing IgE synthesis, IgE production can be further enhanced or inhibited by a number of cytokines. Thus IL-2, IL-5, IL-6, IL-9, and TNF-a synergize with IL-4 and IL-13 to enhance IgE production.

Other cytokines, produced primarily by Th1 cells, tend to downregulate IgE synthesis. The IgE isotype switch is inhibited by interferon (IFN- ) and TGF- . IL-12 and IL-18 inhibit the differentiation of IL-4- producing T cells. IL-8 also inhibits IgE production by purified B cells, but the molecular targets of this process remain unclear. Interestingly, IFN- , IFN- , and IL-12 inhibit IgE synthesis only when tested in a T cell–de- pendent system (e.g., IL-12 does not suppress IgE synthesis by purified B cells), and IL-10 suppresses IgE production only in the presence of monocytes (i.e., it fails to inhibit IL-4-induced IgE synthesis by highly purified B cells in the absence of monocytes).

On a molecular level the initiation and inhibition of IgE synthesis involve a very complex cascade of metabolic pathways that ultimately inhibit or initiate gene transcription. This process uses different groups of enzymes. One of them, signal transducer and activator of transcription 6 (STAT6), promotes IL-4 signaling and the development of Th2 cells.

Figure 3–2 Arachidonic acid metabolic pathways. Arachidonic acid,released as a result of phospholipase action on the cellular membrane, is broken down by two distinct biochemical pathways. The lipoxygenase pathway results in formation of the leukotrienes, whereas

ALLERGIC MEDIATORS

HISTAMINE

Histamine is the major mediator of acute and earlyphase allergic reactions. It is contained in a preformed state within the granules of mast cells and basophils and is formed from the amino acid histidine. Its activities include dilatation and increased permeability of blood vessels, constriction of bronchial airways, stimulation of nerve endings, and secretion of mucus in airways. In extreme cases, histamine-induced intravascular fluid shifts can lead to hypotension and shock.

LEUKOTRIENES

Leukotrienes (LTs) are the major mediators of the late phase and chronic allergic reactions. They are the products of arachidonic acid metabolism and are formed by the action of a lipoxygenase enzymes (Fig. 3–2).They are produced by many cell types, including mast cells, basophils, macrophages, and eosinophils, but on a per cell basis, eosinophils produce more leukotrienes than any other cell type. On a molar basis, leukotrienes are 100 times more potent bronchoconstrictors than histamine. In addition, unlike histamine, whose tissue effects are short-lived, leukotrieneinduced tissue activation lasts a relatively long time. Because of these properties,leukotrienes are thought to be the major mediators of chronic allergic diseases such as asthma.They induce a variety of effects, including constriction of the

the cyclooxygenase pathway generates prostacyclin, thromboxane, and the prostaglandins. (From Allergic Diseases: Diagnosis and Treatment, edited by Phil Lieberman and John A. Anderson, Humana Press,Totowa, New Jersey. Reprinted with permission.)

bronchial airways and increasing the permeability of small blood vessels through stimulation of specific receptors.

Two major classes of these receptors, CysLT1 (for cystinyl leukotriene) and BLT (for LTB4), have been described. Leukotrienes transduce signals via the CysLT1 receptor (previously known as LTD4 receptor). In isolated human airway smooth muscle, LTC4 and LTD4 are of equal potency as contractile agonists at the CysLT1 receptor, whereas LTE4 is less potent.

LTB4 is a natural ligand for the BLT.When activated, the BLT receptor transduces signals that result in chemotaxis and cellular activation.

PROSTAGLANDIN D

Prostaglandin D (PGD) is also formed in human mast cells from the metabolism of arachidonic acid, but through the cyclooxygenase rather than the lipoxygenase pathway. It causes constriction of bronchial airways. Elevated amounts of PGD are found both in nasal lavage fluid and in bronchoalveolar lavage after allergen challenge. However, PGD is only elevated during the early response and does not play a role in maintaining the late response or chronic allergic inflammation.

CYTOKINES

Cytokines are a diverse group of glycoproteins that are synthesized and secreted by many cell types in response

to their activation or injury.As discussed previously, IL-4 and IL-13 cause the upregulation of the IgE response, and IL-12 together with IL-18 (via IFNproduction) downregulates IgE synthesis. In addition, numerous cytokines play important roles in developing and maintaining allergic responses. For instance,TNFand IL-4 cause the enhancement of basophil recruitment. IL-5, IL-3, and GM-CSF promote eosinophil differentiation, activation, and survival. Several chemokines, small specific chemotactic cytokines such as RANTES, and eotaxin are highly selective for eosinophils and play a major role in the recruitment of eosinophils to sites of allergic inflammation. Another chemokine, IL-8, is a major chemoattractant for neutrophils and plays an important role in chronic allergic inflammation.

NEUTRAL PROTEASES

Neutral proteases are present in the secretory granules of mast cells and basophils. They are released after mast cells are activated and can be measured in the serum after systemic allergic reactions.They help in the degradation of proteins by attacking peptide bonds.As described previously, the two major proteases generated by mast cells and basophils are tryptase and chymase. Tryptase is located in both the MCTC cells and MTC subtypes of mast cells, and chymase is located only in the MCTC cells.

PROTEOGLYCANS

The major proteoglycans in mast cells are heparin and chondroitin sulfate A.Their role in allergic reactions is the regulation of mediator release from the granules. They bind both histamine and proteolytic enzymes and are believed to stabilize them until granulation occurs.Although they are released and can be detected after allergic reactions, they do not seem to have any effector functions.The activity of various mediators is summarized in Table 3–1.

ALLERGENS

Airborne allergens are the most important inducers of allergic rhinitis in both children and adults. Table 3–2 presents the most common allergens responsible for the development of allergic symptoms. Sensitization with indoor and outdoor aeroallergens is the most common cause of seasonal and perennial allergic rhinitis.

DUST MITES

House dust mites were first described in 1927 and clearly identified as a cause of asthma in 1967.They are the most important indoor allergens in many areas

TABLE 3–1 CYTOKINES INVOLVED IN ALLERGIC

INFLAMMATION

Ig, immunoglobulin; IFN, interferon; IL, interleukin;Th,T lymphocyte;TNF, tumor necrosis factor.

of the world. Ideal growing conditions for mites are a relative humidity over 50%, temperatures around 70 F, and the presence of shed human skin, which is their major food source.Almost all of the major mite allergens (Der P and Der F) are contained in mite fecal pellets. Because of these growth requirements, bedding has the highest concentration of mite allergens in the home. It has been estimated that there are approximately 250,000 mite fecal pellets in every ounce of dust in a mattress. Most individuals in the developed world therefore spend about 8 hours every night of their entire lives breathing in mite feces. It is therefore not surprising that dust allergy is so prevalent. The majority of patients with perennial allergic rhinitis throughout the world are allergic to dust mites.

ANIMAL ALLERGENS

Although the dander of any mammalian pet can trigger allergic symptoms, cat allergen is probably most common and best studied. Unlike mite allergens, the major cat allergen, Fel d 1, is carried on small particles ( 5µc) and can be detected in the air, on wall surfaces, and on clothing. Other animals, such as birds, cows, and horses, have been reported as sources of allergens for atopic patients.

TABLE 3–2 ALLERGENS RESPONSIBLE FOR PRECIPITATING

ALLERGIC SYMPTOMS

I.Environmental allergens

1.Indoor allergens

a.Dust mites

b.Furry or feathered pets

c.Feathers/down

d.Cockroaches

e.Rodents

2.Outdoor allergens

a.Pollen

b.Mold spores

II.Food allergens

1.Most common

a.Nuts and peanuts

b.Shellfish

c.Eggs

d.Cow’s milk

e.Fish

2.Less common

a.Corn

b.Wheat and other grains

c.Soybean and other legumes

d.Fruits such as strawberry, kiwi, and banana III. Drug allergens

1.Haptens

a.Penicillin and other antibiotics

b.Sulfonamides

c.NSAIDs

2.Proteins and other high-molecular-weight drugs

a.Insulin

b.Psyllium

IV. Occupational allergens

1.Reactive chemicals

a.Anhydrides (phthalic, timelitic, tetrachlorphthalic)

b.Diisocyanates (polyurethane)

c.Wood dusts

2.Proteins and other high-molecular-weight allergens

a.Laboratory animals

b.Enzymes (subtilsin, trypsin)

c.Latex

d.Psyllium

NSAIDs, nonsteroidal anti-inflammatory drugs.

COCKROACHES

Cockroaches are a very important cause of respiratory allergy among impoverished inner-city populations. Cockroach allergens are found on particles of similar

size to mite allergens, and their highest concentration is detected in the kitchen. However, recent data indicate that the bedroom is the most important room in the home in terms of cockroach allergen exposure and resultant sensitization.

MOLDS (FUNGI)

Molds are highly ubiquitous and are common causes of allergic rhinitis. Cladosporium and Alternaria species are the best recognized fungal offenders. However, other types, such as Penicillium,Rhizopus, and Aspergillus, are also frequently implicated as allergens.Although fungi can be detected in the air throughout the year, they are increased during warm, humid seasons. Their seasonal prevalence in the Midwest region of the United States is shown in Fig. 3–3.

Although fungus exposure usually comes from outdoor sources, mold also can be a source of perennial indoor exposure, often growing on shower curtains, in damp basements, and on indoor plants.

POLLENS

Only a minority of plants produce windborne pollen, and even fewer cause nasal allergy. There is a defined sequence of pollen shedding that differs in various climatic regions of the world (Fig. 3-3). In the northern United States, tree pollens of familiar deciduous trees such as oak, maple, elm, and birch appear early in the spring, before the leaves unfold. Grass pollen follows that of trees. Finally, there is a late-summer peak of weeds and ragweed pollen. In warmer areas of the United States, such as the Southeast and Southern California,the grass season may last 6 months or more. In contrast, some areas, such as Southern California and parts of Europe, are devoid of ragweed and do not have a late-summer, “hay fever” season.

INGESTANTS

Although food and drug allergies are common causes of allergic skin, gastrointestinal, and systemic reactions, isolated respiratory reactions due to food and drug allergy are less common. However, there are possible cross-reactions between shrimp and the inhalant or ingested allergens in insect materials such as cockroaches, grasshoppers, and fruit flies. Patients with pollen allergy can develop oral itching on ingestion of cross-reacting fruits. This is termed the oral allergy syndrome and is seen with fruits such as cantaloupe in ragweed-sensitive patients or apple in patients allergic to birch pollen.