global strategy for asthma management and prevention

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GINA_WR_2006.qxp:GINA_WR_2006.qxp 7/20/07 4:12 PM Page 7Diet. The role of diet, particularly breast-feeding, inrelation to the development of asthma has beenextensively studied and, in general, the data reveal thatinfants fed formulas of intact cow's milk or soy protein havea higher incidence of wheezing illnesses in early childhoodcompared with those fed breast milk 88 .Some data also suggest that certain characteristics ofWestern diets, such as increased use of processed foodsand decreased antioxidant (in the form of fruits and vegetables),increased n-6 polyunsaturated fatty acid (found in margarineand vegetable oil), and decreased n-3 polyunsaturatedfatty acid (found in oily fish) intakes have contributed tothe recent increases in asthma and atopic disease 89 .MECHANISMS OF ASTHMAAsthma is an inflammatory disorder of the airways, whichinvolves several inflammatory cells and multiple mediatorsthat result in characteristic pathophysiological changes 21,90 .In ways that are still not well understood, this pattern ofinflammation is strongly associated with airway hyperresponsivenessand asthma symptoms.Airway Inflammation In AsthmaThe clinical spectrum of asthma is highly variable, anddifferent cellular patterns have been observed, but thepresence of airway inflammation remains a consistentfeature. The airway inflammation in asthma is persistenteven though symptoms are episodic, and the relationshipbetween the severity of asthma and the intensity ofinflammation is not clearly established 91,92 . Theinflammation affects all airways including in most patientsthe upper respiratory tract and nose but its physiologicaleffects are most pronounced in medium-sized bronchi.The pattern of inflammation in the airways appears to besimilar in all clinical forms of asthma, whether allergic,non-allergic, or aspirin-induced, and at all ages.Inflammatory cells. The characteristic pattern ofinflammation found in allergic diseases is seen in asthma,with activated mast cells, increased numbers of activatedeosinophils, and increased numbers of T cell receptorinvariant natural killer T cells and T helper 2 lymphocytes(Th2), which release mediators that contribute tosymptoms (Figure 1-4). Structural cells of the airwaysalso produce inflammatory mediators, and contribute to thepersistence of inflammation in various ways (Figure 1-5).Inflammatory mediators. Over 100 different mediators arenow recognized to be involved in asthma and mediate thecomplex inflammatory response in the airways 103 (Figure 1-6).Figure 1-4: Inflammatory Cells in Asthmatic AirwaysMast cells: Activated mucosal mast cells releasebronchoconstrictor mediators (histamine, cysteinyl leukotrienes,prostaglandin D2) 93 . These cells are activated by allergensthrough high-affinity IgE receptors, as well as by osmotic stimuli(accounting for exercise-induced bronchoconstriction). Increasedmast cell numbers in airway smooth muscle may be linked toairway hyperresponsiveness 94 .Eosinophils, present in increased numbers in the airways,release basic proteins that may damage airway epithelial cells.They may also have a role in the release of growth factors andairway remodeling 95 .T lymphocytes, present in increased numbers in the airways,release specific cytokines, including IL-4, IL-5, IL-9, and IL-13,that orchestrate eosinophilic inflammation and IgE production byB lymphocytes 96 . An increase in Th2 cell activity may be due inpart to a reduction in regulatory T cells that normally inhibit Th2cells. There may also be an increase in inKT cells, which releaselarge amounts of T helper 1 (Th1) and Th2 cytokines 97 .Dendritic cells sample allergens from the airway surface andmigrate to regional lymph nodes, where they interact withregulatory T cells and ultimately stimulate production of Th2cells from naïve T cells 98 .Macrophages are increased in number in the airways and maybe activated by allergens through low-affinity IgE receptors torelease inflammatory mediators and cytokines that amplify theinflammatory response 99 .Neutrophil numbers are increased in the airways and sputum ofpatients with severe asthma and in smoking asthmatics, but thepathophysiological role of these cells is uncertain and theirincrease may even be due to glucocorticosteroid therapy 100 .Figure 1-5: Airway Structural Cells Involved in thePathogenesis of AsthmaAirway epithelial cells sense their mechanical environment,express multiple inflammatory proteins in asthma, and releasecytokines, chemokines, and lipid mediators. Viruses and airpollutants interact with epithelial cells.Airway smooth muscle cells express similar inflammatoryproteins to epithelial cells 101 .Endothelial cells of the bronchial circulation play a role inrecruiting inflammatory cells from the circulation into the airway.Fibroblasts and myofibroblasts produce connective tissuecomponents, such as collagens and proteoglycans, that areinvolved in airway remodeling.Airway nerves are also involved. Cholinergic nerves may beactivated by reflex triggers in the airways and causebronchoconstriction and mucus secretion. Sensory nerves,which may be sensitized by inflammatory stimuli includingneurotrophins, cause reflex changes and symptoms such ascough and chest tightness, and may release inflammatoryneuropeptides 102 .DEFINITION AND OVERVIEW 7
GINA_WR_2006.qxp:GINA_WR_2006.qxp 7/20/07 4:12 PM Page 8Figure 1-6: Key Mediators of AsthmaChemokines are important in the recruitment of inflammatorycells into the airways and are mainly expressed in airwayepithelial cells 104 . Eotaxin is relatively selective for eosinophils,whereas thymus and activation-regulated chemokines (TARC)and macrophage-derived chemokines (MDC) recruit Th2 cells.Cysteinyl leukotrienes are potent bronchoconstrictors andproinflammatory mediators mainly derived from mast cells and eosinophils.They are the only mediator whose inhibition has been associatedwith an improvement in lung function and asthma symptoms 105 .Cytokines orchestrate the inflammatory response in asthma anddetermine its severity 106 . Key cytokines include IL-1 and TNF-oc,which amplify the inflammatory response, and GM-CSF, whichprolongs eosinophil survival in the airways. Th2-derived cytokinesinclude IL-5, which is required for eosinophil differentiation andsurvival; IL-4, which is important for Th2 cell differentiation; andIL-13, needed for IgE formation.Histamine is released from mast cells and contributes tobronchoconstriction and to the inflammatory response.Nitric oxide (NO), a potent vasodilator, is produced predominantlyfrom the action of inducible nitric oxide synthase in airway epithelialcells 107 . Exhaled NO is increasingly being used to monitor theeffectiveness of asthma treatment, because of its reportedassociation with the presence of inflammation in asthma 108 .Prostaglandin D2 is a bronchoconstrictor derived predominantlyfrom mast cells and is involved in Th2 cell recruitment to the airways.Structural changes in the airways. In addition to theinflammatory response, there are characteristic structuralchanges, often described as airway remodeling, in theairways of asthma patients (Figure 1-7). Some of thesechanges are related to the severity of the disease and mayresult in relatively irreversible narrowing of the airways 109, 110 .These changes may represent repair in response tochronic inflammation.Figure 1-7: Structural Changes in Asthmatic AirwaysSubepithelial fibrosis results from the deposition of collagen fibersand proteoglycans under the basement membrane and is seen inall asthmatic patients, including children, even before the onset ofsymptoms but may be influenced by treatment. Fibrosis occurs inother layers for the airway wall, with deposition of collagen andproteoglycans.Airway smooth muscle increases, due both to hypertrophy(increased size of individual cells) and hyperplasia (increased celldivision), and contributes to the increased thickness of the airwaywall 111 . This process may relate to disease severity and is causedby inflammatory mediators, such as growth factors.Blood vessels in airway walls proliferate the influence of growthfactors such as vascular endothelial growth factor (VEGF) andmay contribute to increased airway wall thickness.Mucus hypersecretion results from increased numbers of gobletcells in the airway epithelium and increased size of submucosalglands.PathophysiologyAirway narrowing is the final common pathway leading tosymptoms and physiological changes in asthma. Severalfactors contribute to the development of airway narrowingin asthma (Figure 1-8).Figure 1-8: Airway Narrowing in AsthmaAirway smooth muscle contraction in response to multiplebronchoconstrictor mediators and neurotransmitters is thepredominant mechanism of airway narrowing and is largelyreversed by bronchodilators.Airway edema is due to increased microvascular leakage inresponse to inflammatory mediators. This may be particularlyimportant during acute exacerbations.Airway thickening due to structural changes, often termed“remodeling,” may be important in more severe disease and isnot fully reversible by current therapy.Mucus hypersecretion may lead to luminal occlusion (“mucusplugging”) and is a product of increased mucus secretion andinflammatory exudates.Airway hyperresponsiveness. Airway hyperresponsiveness,the characteristic functional abnormality of asthma,results in airway narrowing in a patient with asthma inresponse to a stimulus that would be innocuous in anormal person In turn, this airway narrowing leads tovariable airflow limitation and intermittent symptoms. Airwayhyperresponsiveness is linked to both inflammation and repairof the airways and is partially reversible with therapy.Its mechanisms (Figure 1-9) are incompletely understood.Figure 1-9: Mechanisms of Airway HyperresponsivenessExcessive contraction of airway smooth muscle may resultfrom increased volume and/or contractility of airway smoothmuscle cells 112 .Uncoupling of airway contraction as a result of inflammatorychanges in the airway wall may lead to excessive narrowing of theairways and a loss of the maximum plateau of contraction found innormal ariways when bronchoconstrictor substances are inhaled 113 .Thickening of the airway wall by edema and structural changesamplifies airway narrowing due to contraction of airway smoothmuscle for geometric reasons 114 .Sensory nerves may be sensitized by inflammation, leading toexaggerated bronchoconstriction in response to sensory stimuli.Special MechanismsAcute exacerbations. Transient worsening of asthmamay occur as a result of exposure to risk factors forasthma symptoms, or “triggers,” such as exercise, air8 DEFINITION AND OVERVIEW
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