Pathophysiology of Asthma

INTRODUCTION

This chapter aims to provide a brief overview of diseasemechanisms to integrate some of the detailed informationprovided in earlier chapters into a framework with clinicalrelevance.

Asthma and chronic obstructive pulmonary disease(COPD) are highly complex; many different inflammatorycells and multiple mediators with complex acute andchronic effects on the airways are part of the syndromes.Wenow appreciate that these changes may vary among patientsbecause of genetic variance in susceptibility. There havebeen important advances in our understanding of asthmapathogenesis, resulting from the application of new molecu-lar, cell biological and genetic techniques, and with thedevelopment of new specifically targeted drugs to dissect thecomplex interacting pathways that are activated in asthma;the same has not been true of COPD. Even though we havemade considerable advances in understanding asthma, thereare many fundamental questions about the disease thatremain to be answered. Our understanding of COPD is farless well developed; we understand some of the cellular ele-ments, but how they are integrated to produce the diseasephenotype is not known.

Our views on asthma and COPD have continued toevolve. Although it is recognized that chronic inflammationunderlies the clinical syndromes, it has been hard to definethe precise nature of this inflammation, much less its pri-mary etiology. Nevertheless it is appreciated that the finalconsequence of this chronic inflammatory response is anabnormal control of airway caliber in vivo in asthma. In con-trast, the evolution of understanding in COPD has beenmuch slower; key insights are sought which will open up theunderstanding of this complex disorder.

ASTHMA AS AN INFLAMMATORYDISEASE

It had been recognized for many years that patients whodie of asthma attacks have grossly inflamed airways. Theairway lumen is occluded by a tenacious mucus plug com-posed of plasma proteins exuded from airway vessels andmucus glycoproteins secreted from surface epithelial cells.The airway wall is edematous and infiltrated with inflam-matory cells, which are predominantly eosinophils and Tlymphocytes.1 The airway epithelium is invariably shed in apatchy manner and clumps of epithelial cells are found inthe airway lumen. Occasionally there have been opportuni-ties to examine the airways of asthmatic patients who die inaccidents thought to be unrelated to their asthma. In thissetting inflammatory changes have been observed but theyare less marked than those observed in patients with activeasthma.2 These studies also reveal that the inflammation inasthmatic airways involves not only the trachea andbronchi, but extends to the terminal bronchioles;3 someinvestigators have shown inflammatory cells in theparenchyma.4

It has also been possible to examine the airways of asth-matic patients by fiberoptic and rigid bronchoscopy, bybronchial biopsy, and by bronchoalveolar lavage. Directbronchoscopic examination reveals that the airways of asth-matic patients are often erythematous and swollen, indicat-ing acute inflammation. Lavage of the airways has revealedan increase in the numbers of lymphocytes, mast cells, andeosinophils and evidence for activation of macrophages incomparison with nonasthmatic controls. Biopsies have pro-vided evidence for increased numbers and activation of mastcells, macrophages, eosinophils, and T lymphocytes. Thesechanges are found even in patients with mild asthma whohave few symptoms,5 suggesting that inflammation may befound in all asthmatic patients who are symptomatic.Indeed, inflammation may even be present in episodic asth-matics at a time when there are no symptoms, or in atopic

Pathophysiology of Asthma

Peter J. BarnesNational Heart and Lung Institute, Imperial College of Science, Technology andMedicine, London, UK

Jeffrey M. DrazenDepartment of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Chapter

35

35 Chapter 0935 6/3/02 4:45 pm Page 343

individuals who are not asthmatic. This suggests that theinflammation needs to reach a certain threshold to result insymptoms.

AIRWAY HYPERRESPONSIVENESS

The relationship between inflammation and clinical symp-toms of asthma is not clear. There is evidence that thedegree of inflammation is loosely related to airway hyperre-sponsiveness (AHR), as measured by histamine or metha-choline challenge. The degree of inflammation does notclearly correspond to asthma severity, however. This sug-gests that other factors, such as structural changes in theairway wall, are important.The increased airway responsive-ness in asthma is a striking physiological abnormality that ispresent even when airway function is normal. It is likely thatthere are several factors that underlie this increased respon-siveness to constrictor agents, particularly those that actindirectly by releasing bronchoconstrictor mediators fromairway cells. AHR may be due to increased release of medi-ators (such as histamine and leukotrienes from mast cells),abnormal behavior of airway smooth muscle, thickening ofthe airway wall by reversible (edema) and irreversible (air-way smooth muscle thickening, fibrosis) elements. Airwaysensory nerves may also contribute importantly to symp-toms, such as cough and chest tightness, as the nervesbecome sensitized by the chronic inflammation in theairways.

In hyperresponsive airways, triggers which would not nor-mally narrow the airways, such as exercise, have a bron-choconstrictor effect (Fig. 35.1). However, there is reasonto believe that products of the inflammatory response mayalso directly lead to an increase in asthma symptoms, suchas cough and chest tightness. These effects, which are the

equivalent of pain in other inflammatory diseases, may bemediated by sensitization and activation of airway sensorynerve endings.

Although most attention has been focused on the acuteinflammatory changes seen in asthmatic airways (bron-choconstriction, plasma exudation, mucus secretion),asthma is a chronic disease, persisting over many years inmost patients. Superimposed on this chronic inflammatorystate are acute inflammatory episodes, which correspond toexacerbations of asthma. It is clearly important to under-stand the mechanisms of acute and chronic inflammation inasthmatic airways and to investigate the long-term conse-quences of this chronic inflammation on airway function.

INFLAMMATORY CELLS

Many different inflammatory cells are involved in asthma,although the precise role of each cell type is not yet certain(Fig. 35.2). It is evident that no single inflammatory cell isable to account for the complex pathophysiology of asthma,but some cells predominate in asthmatic inflammation.Theinflammation in asthmatic airways differs strikingly fromthat observed in COPD, where there is a predominance ofmacrophages, cytotoxic (CD8�) T lymphocytes, andneutrophils, although both of these common diseases maycoexist in some patients.6,7

Mast cellsMast cells are clearly important in initiating the acutebronchoconstrictor responses to allergen and probably toother indirect stimuli, such as exercise and hyperventilation(via osmolality or thermal changes) and fog.We now appre-ciate that mast cell numbers are increased in sensitizedhuman airway smooth muscle.8 Treatment of asthmaticpatients with prednisone results in a decrease in the number oftryptase-only positive mast cells.9 Furthermore, the numberof mast cells in induced sputum in patients with seasonalallergic rhinitis is related to the degree of methacholineresponsiveness.10 Finally there are data implicating mast celltryptase as an important component of airway remodelingas this mast cell product stimulates human lung fibroblastproliferation.11 Mast cells also secrete certain cytokines,such as interleukin (IL)-4 that may be involved in maintain-ing the allergic inflammatory response.12

However, there are questions about the role of mast cellsin more chronic inflammatory events, and it seems moreprobable that other cells, such as macrophages, eosinophils,and T lymphocytes, are more important in the chronicinflammatory process, including AHR. Classically mast cellsare activated by allergens through an IgE-dependent mech-anism. The importance of IgE in the pathophysiology ofasthma has been highlighted by recent clinical studies withhumanized anti-IgE antibodies, which inhibit IgE-mediatedeffects. Although anti-IgE antibody results in a reduction incirculating IgE to undetectable levels, this treatment resultsin minimal clinical improvement in patients with severe

344 Asthma and Chronic Obstructive Pulmonary Disease344

AllergensSensitizers

VirusesAir pollutants??

Symptoms

Chesttightness

CoughDyspneaWheeze

INFLAMMATION‘Chronic eosinophillic

bronchitis’

AIRWAYHYPERRESPONSIVENESS

TriggersAllergensExerciseCold air

SO2

Particulates

Fig. 35.1. Inflammation in the airways of asthmatic patients leads to air-way hyperresponsiveness and symptoms.

35 Chapter 0935 6/3/02 4:45 pm Page 344

steroid-dependent asthma.13 Interestingly, treatment withthe anti-IgE monoclonal did allow reduction of the dose ofsteroids required for asthma control. This suggests that themechanisms whereby IgE leads to airway obstruction aresteroid-sensitive.

MacrophagesMacrophages, which are derived from blood monocytes,may traffic into the airways in asthma and may be activatedby allergen via low-affinity IgE receptors (FceRII).14 Theenormous immunological repertoire of macrophages allowsthese cells to produce many different products, including alarge variety of cytokines that may orchestrate the inflam-matory response. Macrophages have the capacity to initiatea particular type of inflammatory response via the release ofa certain pattern of cytokines. Macrophages may bothincrease and decrease inflammation, depending on thestimulus. Alveolar macrophages normally have a suppressiveeffect on lymphocyte function, but this may be impaired inasthma after allergen exposure.15 Macrophages may there-fore play an important anti-inflammatory role, preventingthe development of allergic inflammation. Macrophagesmay also act as antigen-presenting cells which process aller-gen for presentation to T lymphocytes, although alveolarmacrophages are far less effective in this respect thanmacrophages from other sites, such as the peritoneum.16

Dendritic cellsBy contrast, dendritic cells (which are specializedmacrophage-like cells in the airway epithelium) are veryeffective antigen-presenting cells,16,17 and may therefore playa very important role in the initiation of allergen-inducedresponses in asthma. Dendritic cells take up allergens,process them to peptides, and migrate to local lymph nodeswhere they present the allergenic peptides to uncommittedT lymphocytes, to program the production of allergen-specific T cells. Immature dendritic cells in the respiratorytract promote Th2 cell differentiation and require cytokinessuch as IL-12 and TNF-a to promote the normally prepon-derant Th1 response.18

EosinophilsEosinophil infiltration is a characteristic feature of asthmaticairways and differentiates asthma from other inflammatoryconditions of the airway. Indeed, asthma might more accu-rately be termed “chronic eosinophilic bronchitis” (a termfirst used as early as 1916). Allergen inhalation results in amarked increase in eosinophils in bronchoalveolar lavage(BAL) fluid at the time of the late reaction, and there is acorrelation between eosinophil counts in peripheral blood orbronchial lavage and AHR. Eosinophils are linked to thedevelopment of airway hyperresponsiveness through therelease of basic proteins and oxygen-derived free radicals.19

An important area of research is now concerned with themechanisms involved in recruitment of eosinophils into asth-matic airways. Eosinophils are derived from bone marrowprecursors. After allergen challenge eosinophils appear inBAL fluid during the late response, and this is associatedwith a decrease in peripheral eosinophil counts and with theappearance of eosinophil progenitors in the circulation.Thesignal for increased eosinophil production is presumablyderived from the inflamed airway. Eosinophil recruitmentinitially involves adhesion of eosinophils to vascularendothelial cells in the airway circulation, their migrationinto the submucosa, and their subsequent activation. Therole of individual adhesion molecules, cytokines, and medi-ators in orchestrating these responses has been extensivelyinvestigated.

Adhesion of eosinophils involves the expression ofspecific glycoprotein molecules on the surface of eosinophils(integrins) and their expression of such molecules as inter-cellular adhesion molecule-1 (ICAM-1) on vascularendothelial cells. An antibody directed at ICAM-1 markedlyinhibits eosinophil accumulation in the airways after allergenexposure and also blocks the accompanying hyperrespon-siveness.20 However, ICAM-1 is not selective for eosinophilsand cannot account for the selective recruitment ofeosinophils in allergic inflammation. The adhesion mole-cules VLA4 expressed on eosinophils and VCAM-1 appearto be more selective for eosinophils,21 and IL-4 increases theexpression of VCAM-1 on endothelial cells.22 Eosinophil

345Pathophysiology of Asthma 345

Fig. 35.2. Many cells and mediators are involved in asthma and lead to several effects on the airways.

Inflammatory cellsMast cellsEosinophilsTh2 cellsBasophilsNeutrophilsPlatelets

Structural cellsEpithelial cellsSm muscle cellsEndothelial cellsFibroblastNerves

EffectsBronchospasmPlasma exudationMucus secretionAHRStructural changes

MediatorsHistamineLeukotrienesProstanoidsPAFKininsAdenosineEndothelinsNitric oxideCYTOKINESCHEMOKINES

35 Chapter 0935 6/3/02 4:45 pm Page 345

migration may be due to the effects of lipid mediators, suchas leukotrienes23 and possibly PAF, to the effects ofcytokines, such as GM-CSF and IL-5 which may be veryimportant for the survival of eosinophils in the airways andmay “prime” eosinophils to exhibit enhanced responsive-ness. Eosinophils from asthmatic patients show exaggeratedresponses to PAF and phorbol esters, compared witheosinophils from atopic nonasthmatic individuals.24 This isfurther increased by allergen challenge,25 suggesting thatthey may have been primed by exposure to cytokines in thecirculation.

There are several mediators involved in the migration ofeosinophils from the circulation to the surface of the airway.The most potent and selective agents appear to bechemokines, such as RANTES, eotaxin, and MCP-4, thatare expressed in epithelial cells.26,27 There appears to be aco-operative interaction between IL-5 and chemokines, sothat both cytokines are necessary for the eosinophilicresponse in airways.28 Once recruited to the airways,eosinophils require the presence of various growth factors,of which GM-CSF and IL-5 appear to be the most impor-tant.29 In the absence of these growth factors eosinophilsundergo programmed cell death (apoptosis).

Recently a humanized monoclonal antibody to IL-5 hasbeen administered to asthmatic patients;30 and, as in animalstudies, there is a profound and prolonged reduction in cir-culating eosinophils. Although the infiltration of eosinophilsinto the airway after inhaled allergen challenge is completelyblocked, there is no effect on the response to inhaledallergen and no reduction in AHR. These data question thepivotal role of eosinophils in asthma.

NeutrophilsThe eosinophil has been the recipient of current attention asan effector cell in asthma, but attention has been returningto the role of neutrophils.31 Although neutrophils are not apredominant cell type observed in the airways of patientswith mild-to-moderate chronic asthma, they appear to be amore prominent cell type in airways and induced sputum ofpatients with more severe asthma.32 Also in patients who diesuddenly of asthma, large numbers of neutrophils are foundin the airways,33 although this may reflect the rapid kineticsof neutrophil recruitment compared to eosinophil inflam-mation. Whether the selective recruitment of neutrophilsoccurs as a result of high doses of inhaled corticosteroids orreflects the pathophysiology of severe asthma is currentlyunknown. Our appreciation of the importance of neutrophilsas effector cells in more severe forms of asthma is just begin-ning; in the future we can expect a more complete under-standing of the role of neutrophils in the asthmatic diathesis.

T lymphocytesT lymphocytes play a very important role in coordinatingthe inflammatory response in asthma through the release ofspecific patterns of cytokines, resulting in the recruitmentand survival of eosinophils and in the maintenance of mastcells in the airways. T lymphocytes are coded to express a

distinctive pattern of cytokines, which are similar to thatdescribed in the murine Th2 type of T lymphocytes, whichcharacteristically express IL-4, IL-5, and IL-13.34 This pro-gramming of T lymphocytes is presumably due to antigenpresenting cells such as dendritic cells, which may migratefrom the epithelium to regional lymph nodes or which interactwith lymphocytes resident in the airway mucosa. The naiveimmune system is skewed to express theTh2 phenotype; datanow indicate that children with atopy are more likely to retainthis skewed phenotype than are normal children.35

There is some evidence that early infections or exposureto endotoxins might promote Th1-mediated responses topredominate and that a lack of infection or a clean environ-ment in childhood may favour Th2 cell expression and thusatopic diseases.36–38 Indeed, the balance between Th1 cellsand Th2 cells is thought to be determined by locally releasedcytokines, such as IL-12, which tip the balance in favor ofTh1 cells, or IL-4 or IL-13 which favor the emergence ofTh2 cells (Fig. 35.3). There is some evidence that steroidtreatment may differentially effect the balance between IL-12 and IL-13 expression.39 Data from murine models ofasthma40–42 have strongly suggested that IL-13 is bothnecessary and sufficient for induction of the asthmaticphenotype. One of the most important areas of asthmaresearch in the next few years will be to establish the impor-tance of IL-13 in the induction of the Th2 phenotype andasthma in humans.

BasophilsThe role of basophils in asthma is uncertain, as these cellshave previously been difficult to detect by immunocyto-chemistry.12 Using a basophil-specific marker, a smallincrease in basophils has been documented in the airways ofasthmatic patients, with an increased number after allergenchallenge. However, these cells are far outnumbered byeosinophils.43


Eosinophil

Mast cell

Antigen presenting cellDendritic cell, macrophage

Allergen

Th1

Thp

Th2

IL-2IFN-γ

IL-4IL-13

IgE

IL-12IL-18

IFN-γ

IL-5

IL-4

CD28TCR

MHCI B7-2Allergentpeptide

Fig. 35.3. Asthma is characterized by a preponderance of Th2 over Th1cells.

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Pathophysiology of Asthma 347

Structural cells Structural cells of the airways, including epithelial cells, fibroblasts, and even airway smooth muscle cells may also be an important source of inflammatory mediators, such as cytokines and lipid mediators in asthma.''''"''* Indeed, because structural cells far outnumber inflammatory cells they may become the major source of mediators driving chronic inflammation in asthmatic airways. In addition, epithelial cells may have a key role in translating inhaled environmental signals into an airway inflammatory response and are probably a major target cell for inhaled glucocorticoids (Fig. 35.4).

INFLAMMATORY MEDIATORS

Many different mediators have been implicated in asthma. They may have a variety of effects on the airways, which could account for the pathological features of asthma'"'''* (Fig. 35.2). Mediators such as histamine, prostaglandins, and leukotrienes contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells. Because each mediator has many effects the role of individual mediators in the pathophysiology of asthma is not yet clear. Although the multiplicity of mediators makes it unlikely that preventing the synthesis or action of a single mediator will have a major impact in clinical asthma, recent clinical studies with antileukotrienes suggest that cysteinyl-leukotrienes have a clinically important effect.

The cysteinyl-leukotrienes LTC4, LTD4, and LTE4 are potent constrictors of human airways and have been

reported to increase AHR and may play an important role in asthma''''^" (see Chapter 24). The recent development of potent specific leukotriene antagonists has made it possible to evaluate the role of these mediators in asthma. Potent LTD4 antagonists protect (by about 50%) against exercise-and allergen-induced bronchoconstriction,^'"^^ suggesting that leukotrienes contribute to bronchoconstrictor responses. Combined treatment with an antihistamine and an antileukotriene is particularly effective.^* Chronic treatment with antileukotrienes improves lung function and symptoms in asthmatic patients, although the degree of lung function improvement is not as great as that seen with an inhaled glucocorticoid. It is only through the use of specific antagonists that the role of individual mediators of asthma may be defined. In the future, pharmaceuticals with specific targets of action will be of special value in providing patho-biological insights into the basic mechanisms of asthma; their potential role in the treatment of asthma remains to be determined.

For example, platelet-activating factor (PAF) is a potent inflammatory mediator that mimics many of the features of asthma, including eosinophil recruitment and activation and induction of AHR; yet even potent PAF antagonists, such as modipafant, do not control asthma symptoms, at least in chronic asthma.^'"*" However, genetic studies in Japan, where there is a high frequency of a genetic mutation which disables the PAF metabolizing enzyme, PAF acetyl hydrolase, have shown that there is an association between the presence of the mutant form of the enzyme and severe asthma.*''*^ These data suggest that there may be certain conditions associated with a significant role for PAF in asthma.

Viruses O2, NO2

Allergens Viruses

FCERII ° •= - > Macrophage

^P<MiMiMi^

TNF-a, IL-ip, IL-6

Airway epithelial cells

GM-CSF Eotaxin

RANTES MCP-4

PDGF

RANTES IL-16

Eosinophil survival

chemotaxis

Lymphocyte activation

Smooth muscle hyperplasia

Fibroblast activation

Fig. 35.4. Airway epithelial cells may play an active role in asthmatic inflammation through the release of many inflammatory mediators and cytokines.

CytokinesCytokines are increasingly recognized to be important inchronic inflammation and play a critical role in orches-trating the type of inflammatory response63 (Fig. 35.5).Many inflammatory cells (macrophages, mast cells,eosinophils, and lymphocytes) are capable of synthesizingand releasing these proteins, and structural cells such asepithelial cells and endothelial cells may also release avariety of cytokines and may therefore participate in thechronic inflammatory response.64 While inflammatorymediators like histamine and leukotrienes may be impor-tant in the acute and subacute inflammatory responsesand in exacerbations of asthma, it is likely that cytokinesplay a dominant role in chronic inflammation. Almostevery cell is capable of producing cytokines under certainconditions.

Research in this area is hampered by a lack of specificantagonists, although important observations have beenmade using specific neutralizing antibodies. The cytokineswhich appear to be of particular importance in asthmainclude the lymphokines secreted by T lymphocytes:

• IL-3, which is important for the survival of mast cells intissues;

• IL-4, which is critical in switching B-lymphocytes to pro-duce IgE and for expression of VCAM-1 on endothelialcells;

• IL-13, which acts similarly to IL-4 in IgE switching;• IL-5 which is of critical importance in the differentiation,

survival and priming of eosinophils.

There is increased gene expression of IL-5 in lymphocytesin bronchial biopsies of patients with symptomatic asthma.65

The role of an IL-5 in eosinophil recruitment in asthma hasbeen confirmed in a study in which administration of ananti-IL-5 antibody to asthmatic patients was associated witha decrease in eosinophil counts in the blood and BALfluid.30 Interestingly in this small study there was no effecton the physiology of the allergen-induced asthmaticresponse; although this is not the last word on eosinophils inasthma, it provides evidence that the eosinophil, as recruitedby IL-5, is not the major pathogenetic cell in asthma.Another Th2 cytokine, IL-9, may play a critical role issensitizing responses to the cytokines IL-4 and IL-5.66–68

Other cytokines, such as IL-1b, IL-6, TNF-a, and GM-CSF, are released from a variety of cells, includingmacrophages and epithelial cells, and may be important inamplifying the inflammatory response. TNF-a may be anamplifying mediator in asthma and is produced in increasedamounts in asthmatic airways.69 Inhalation of TNF-aincreased airway responsiveness in normal individuals.70

TNF-a and IL-1b both activate the proinflammatory tran-scription factors, nuclear factor-jB (NF-jB) and activatorprotein-1 (AP-1) which then switch on many inflammatorygenes in the asthmatic airway.

ComplementAlthough the role of complement has been largely dis-counted in asthma, studies in mice harboring a targeteddeletion of the C5a receptor had diminished bronchialhyperresponsiveness induced after allergen challenge.71


Fig. 35.5. The cytokine network in asthma. Many inflammatory cytokines are released from inflammatory and structural cells in the airway andorchestrate and perpetuate the inflammatory response.

Eosinophil

Smooth muscleTh0 cell

Th2 cell

Dendritic cell

Epithelial cell

Mast cell B lymphocyte

Monocyte

Macrophage

MCP-1

GM-CSFRANTES

IL-5, GM-CSF

IL-3

IL-10

IL-12

GM-CSF

IL-4IL-13

IL-4IL-13

GM-CSF, IL-6, IL-11Eotaxin, RANTES, IL-8

IL-5

IgE

IL-1βTNF-α

Allergen

TNF-αIL-4IL-5

�

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Genetic linkage studies in mice have linked regions of themouse genome containing the gene for C5a to the pheno-type of airway hyperresponsivenes.72 Furthermore, thecomplement peptide C5a has been recovered from BALfluid of patients after allergen challenge.71

Oxidative stressAs in all inflammatory diseases, there is increased oxidativestress in asthma as activated inflammatory cells, such asmacrophages and eosinophils, produce reactive oxygenspecies. Evidence for increased oxidative stress in asthma isprovided by the increased concentrations of 8-isoprostane(a product of oxidized arachidonic acid) in exhaled breathcondensates,73 and increased ethane (a product of oxidativelipoid peroxidation) in exhaled breath of asthmaticpatients.74 Increased oxidative stress is related to diseaseseverity and may amplify the inflammatory response andreduce responsiveness to corticosteroids.

EndothelinsEndothelins are potent peptide mediators that are vasocon-strictors and bronchoconstrictors.75 Endothelin-1 levels areincreased in the sputum of patients with asthma; these lev-els are modulated by allergen exposure and steroid treat-ment.76–78 Endothelins also induce airway smooth musclecell proliferation and promote a profibrotic phenotype andmay therefore play a role in the chronic inflammation ofasthma. Endothelin has an inhibitory effect on the expression

of inducible nitric oxide synthase (NOS) and thus may mod-ify the primary microenvironment of the asthmatic airway.

Nitric oxideNitric oxide (NO) is produced by several cells in the airwayby NO synthases.79 Although the cellular source of NOwithin the lung is not known, inferences based on mathe-matical models suggest that it is the large airways which arethe source of NO.80 Current data indicate that the level ofNO in the exhaled air of patients with asthma is higher thanthe level of NO in the exhaled air of normal subjects.81–83

The elevated levels of NO in asthma are more likely reflec-tive of an as yet to be identified inflammatory mechanismthan of a direct pathogenetic role of this gas in asthma.84,85

Current data suggest that the level of NO in exhaled airreflects local airway pH which may be the primary factormodified by the inflammatory processes of asthma.86 Thecombination of increased oxidative stress and NO may leadto the formation of the potent radical peroxynitrite, that mayresult in nitrosylation of proteins in the airways.87

EFFECTS OF INFLAMMATION ON THEAIRWAYS

The chronic inflammatory response has several effects on thetarget cells of the airways, resulting in the characteristic patho-physiological changes associated with asthma (Fig. 35.6).


Th2 cell

Mast cell

Neutrophil

Myofibroblast

Eosinophil

Epithelial shedding

Nerve activation

Plasma leakEdema

Subepithelialfibrosis

Sensory nerveactivation

Cholinergicreflex

BronchoconstrictionHypertrophy/hyperplasia

MucushypersecretionHyperplasia

VasodilatationNew vessels

Macrophage/dendritic cell

Allergen

Mucus plug

Fig. 35.6. The pathophysiology of asthma is complex, with participation of several interacting inflammatory cells which result in acute and chronicinflammatory effects on the airway.

35 Chapter 0935 6/3/02 4:45 pm Page 349

Asthma may be regarded as a disease with continuousinflammation and repair proceeding simultaneously. Impor-tant advances continue to be made in our understanding ofthese changes; but despite these new insights, the relation-ship between chronic inflammatory processes and asthmasymptoms is often not clear.

Airway epitheliumAirway epithelial shedding may be important in contribut-ing to airway hyperresponsiveness and may explain howseveral different mechanisms, such as ozone exposure, cer-tain virus infections, chemical sensitizers and allergen expo-sure can lead to its development, since all these stimuli maylead to epithelial disruption. Epithelium may be shed as aconsequence of inflammatory mediators, such as eosinophilbasic proteins and oxygen-derived free radicals, togetherwith various proteases released from inflammatory cells.Epithelial cells are commonly found in clumps in the BALfluid or sputum (Creola bodies) of asthmatics, suggestingthat there has been a loss of attachment to the basal layer orbasement membrane. Epithelial damage may contribute toAHR in a number of ways, including:

• loss of its barrier function to allow penetration ofallergens;

• loss of enzymes (such as neutral endopeptidase) whichnormally degrade inflammatory mediators;

• loss of a relaxant factor (so called epithelial-derivedrelaxant factor);

• exposure of sensory nerves which may lead to reflex neuraleffects on the airway.

FibrosisThe basement membrane in asthma appears on lightmicroscopy to be thickened; on closer inspection by electronmicroscopy it has been demonstrated that this apparentthickening is due to subepithelial fibrosis with deposition oftype III and V collagen below the true basement membrane.Data from a number of investigative groups show that thethickness of the deposited collagen is related to airwayobstruction and airway responsiveness.88–90 The mechanismof the collagen deposition is not known. However, it isknown that several profibrotic cytokines, including TGF-band PDGF, and mediators such as endothelin-1, can be pro-duced by epithelial cells or macrophages in the inflamed air-way.64 There are novel findings which indicate that evensimple mechanical manipulations can alter the phenotype ofairway epithelial cells in a profibrotic fashion.91 The role offibrosis in asthma is unclear, as subepithelial fibrosis hasbeen observed even in mild asthmatics at the onset ofdisease; it is not certain whether the collagen deposition hasany functional consequences. Nevertheless, substantialattention has been paid to these histological changes. Someinvestigators suggest that the changes are the key patho-genetic changes leading to irreversible loss of lung functionin patients with asthma, while others argue that the findingsare of little consequence.92,93 This is an area of active

research and greater understanding of these changes is likelyover the next few years.

Airway smooth muscleThere is still debate about the role of abnormalities in air-way smooth muscle in asthmatic airways. In vitro, airwaysmooth muscle from asthmatic patients usually shows noincreased responsiveness to spasmogens. Reduced respon-siveness to b-agonists has also been reported in post-mortem or surgically removed bronchi from asthmatics,although the number of b-receptors is not reduced, suggest-ing that b-receptors have been uncoupled.94 These abnor-malities of airway smooth muscle may be a reflection of thechronic inflammatory process. For example, it is establishedthat chronic exposure to inflammatory cytokines, such asIL-1b, can downregulate the response to b2-adrenergicagonists.95 Interestingly, steroid treatment prevents theeffects of IL-1b on the effects of b-agonists.96 Furthermore,the reduced b-adrenergic responses in airway smoothmuscle could be due to phosphorylation of the stimulatoryG protein coupling b-receptors to adenylyl cyclase, resultingfrom the activation of protein kinase C by the stimulation ofairway smooth muscle cells by inflammatory mediators andto increased activity of the inhibitory G protein (Gi) inducedby proinflammatory cytokines.97,98

Inflammatory mediators may modulate the ion channelsthat serve to regulate the resting membrane potential of air-way smooth muscle cells, thus altering the level of excitabil-ity of these cells. Furthermore, modulation of the activationkinetics of other ion channels by key inflammatory media-tors can lead to altered contractile characteristics of smoothmuscle.

In asthmatic airways there is also a characteristic hyper-trophy and hyperplasia of airway smooth muscle,99 which ispresumably the result of stimulation of airway smoothmuscle cells by various growth factors, such as PDGF, orendothelin-1 released from inflammatory cells.

Vascular responsesVasodilatation occurs in inflammation, yet little is knownabout the role of the airway circulation in asthma. This ispartly because of the difficulties involved in measuring air-way blood flow. Recent studies using an inhaled absorbablegas have demonstrated an increased airway mucosal bloodflow in asthma.100 The bronchial circulation may play animportant role in regulating airway caliber, since an increasein the vascular volume may contribute to airway narrowing.Increased airway blood flow may be important in removinginflammatory mediators from the airway, and may play arole in the development of exercise-induced asthma.101

Increased shear stress due to high expiratory pressures maylead to gene transduction and enhanced production of nitricoxide by type III (endothelial) NO synthase.102,103 There mayalso be an increase in the number of blood vessels in asth-matic airways as a result of angiogenesis.104,105

Microvascular leakage is an essential component of theinflammatory response and many of the inflammatory


35 Chapter 0935 6/3/02 4:45 pm Page 350

mediators implicated in asthma produce this leakage.106,107

There is good evidence for microvascular leakage in asthma,and it may have several consequences on airway function,including increased airway secretions, impaired mucociliaryclearance, formation of new mediators from plasma pre-cursors (such as kinins), and mucosal edema which maycontribute to airway narrowing and increased airwayhyperresponsiveness.108,109

Mucus hypersecretionMucus hypersecretion is a common inflammatory responsein secretory tissues. Increased mucus secretion contributesto the viscid mucus plugs which occlude asthmatic airways,particularly in fatal asthma. There is evidence for hyperpla-sia of submucosal glands which are confined to large air-ways, and of increased numbers of epithelial goblet cells.This increased secretory response may be due to inflamma-tory mediators acting on submucosal glands and due tostimulation of neural elements.Two of the critical cytokinesthought to be of importance in creating the immuneenvironment of asthma, IL-4 and IL-13, have been shown toparticipate in mucus hypersecretion in experimental modelsof asthma.42,110 The role of hypertrophy and hyperplasia ofthe mucosecretory apparatus in asthma is not known, butthese recent findings should stimulate a reassessment ofboth the anatomic changes in the mucus-secreting cells aswell as the study of the secreted mucus itself in asthma.

Neural effectsThere has recently been a revival of interest in neural mech-anisms in asthma.111 Autonomic nervous control of the air-ways is complex; in addition to classical cholinergic andadrenergic mechanisms, nonadrenergic noncholinergic(NANC) nerves and several neuropeptides have been iden-tified in the respiratory tract.112–114 Several studies haveinvestigated the possibility that defects in autonomic controlmay contribute to AHR in asthma, and abnormalities ofautonomic function, such as enhanced cholinergic and a-adrenergic responses or reduced b-adrenergic responses,have been proposed. Current thinking suggests that theseabnormalities are likely to be secondary to the disease,rather than primary defects.111 It is possible that airwayinflammation may interact with autonomic control byseveral mechanisms.

Inflammatory mediators may act on various prejunctionalreceptors on airway nerves to modulate the release ofneurotransmitters.115,116 Thus thromboxane and PGD2

facilitate the release of acetylcholine from cholinergicnerves in canine airways, whereas histamine inhibits cholin-ergic neurotransmission at both parasympathetic gangliaand postganglionic nerves via H3 receptors. Inflammatorymediators may also activate sensory nerves, resulting inreflex cholinergic bronchoconstriction or release of inflam-matory neuropeptides. Inflammatory products may alsosensitize sensory nerve endings in the airway epithelium, sothat the nerves become hyperalgesic. Hyperalgesia and pain(dolor) are cardinal signs of inflammation, and in the

asthmatic airway may mediate cough and chest tightness,which are such characteristic symptoms of asthma. Theprecise mechanisms of hyperalgesia are not yet certain, butmediators such as prostaglandins, certain cytokines, andneurotrophins may be important. Neurotrophins, whichmay be released from various cell types in peripheral tissues,may cause proliferation and sensitization of airway sensorynerves.117

Bronchodilator nerves which are nonadrenergic areprominent in human airways, and it has been suggested thatthese nerves may be defective in asthma.118 In animal air-ways, vasoactive intestinal peptide (VIP) has been shown tobe a neurotransmitter of these nerves, and a striking absenceof VIP-immunoreactive nerves has been reported in thelungs from patients with severe fatal asthma.119 However, itis likely that this loss of VIP immunoreactivity is due todegradation by tryptase released from degranulating mastcells in the airways of asthmatics. In human airways, thebronchodilator neurotransmitter appears to be nitricoxide.120 In guinea-pigs,VIP administration can lead to NOrelease,121 thus there may be a link between VIP and NO inhumans.

Airway nerves may also release neurotransmitters whichhave inflammatory effects.Thus neuropeptides such as sub-stance P (SP), neurokinin A, and calcitonin-gene relatedpeptide may be released from sensitized inflammatorynerves in the airways which increase and extend the on-going inflammatory response.122 There is evidence for anincrease in SP-immunoreactive nerves in airways ofpatients with severe asthma,123 which may be due to prolif-eration of sensory nerves and increased synthesis ofsensory neuropeptides as a result of nerve growth factorsreleased during chronic inflammation – although this hasnot been confirmed in milder asthmatic patients.124 Theremay also be a reduction in the activity of enzymes, such asneutral endopeptidase, which degrade neuropeptides suchas SP.125 There is also evidence for increased gene expres-sion of the receptor which mediates the inflammatoryeffects of SP.126

Thus chronic asthma may be associated with increasedneurogenic inflammation, which may provide a mechanismfor perpetuating the inflammatory response even in theabsence of initiating inflammatory stimuli.

Acute and chronic inflammationAsthma is characterized by acute inflammatory episodes,which may occur after upper respiratory tract virus infec-tions or exposure to a large amount of inhaled allergen,resulting in bronchoconstriction, plasma exudation, edema,and mucus secretion. However, asthma is also a chronicinflammatory process, partly driven by exposure to low-levelenvironmental allergens such as house dust mite and molds,and this may result in structural changes in the airway walls(remodeling) that lead to progressive narrowing of airways.This may account for the accelerated decline in airway func-tion seen in asthmatic patients over several years.127,128 Thesechanges include:


35 Chapter 0935 6/3/02 4:45 pm Page 351

• increased thickness of airway smooth muscle;• fibrosis (which is predominantly subepithelial);• increased mucus-secreting cells;• increased numbers of blood vessels (angiogenesis).

It is not known if these changes are reversible with therapy.These changes may occur in some patients to a greaterextent than others and may be increased by other factorssuch as concomitant cigarette smoking. It is likely thatgenetic factors will influence the extent of remodeling thatoccurs in individual patients.

TRANSCRIPTION FACTORS

The chronic inflammation of asthma is due to increasedexpression of multiple inflammatory proteins (cytokines,enzymes, receptors, adhesion molecules). In many casesthese inflammatory proteins are induced by transcriptionfactors, DNA binding factors that increase the transcriptionof selected target genes129,130 (Fig. 35.7).

One transcription factor that may play a critical role inasthma is nuclear factor-kappa B (NF-jB) which can be acti-vated by multiple stimuli, including protein kinase C activa-tors, oxidants, and proinflammatory cytokines (such as IL-1band TNF-a).131 There is evidence for increased activation ofNF-jB in asthmatic airways, particularly in epithelial cells

and macrophages.132 NF-jB regulates the expression of sev-eral key genes that are overexpressed in asthmatic airways,including proinflammatory cytokines (IL-1b, TNF-a, GM-CSF), chemokines (RANTES, MIP-1a, eotaxin), adhesionmolecules (ICAM-1,VCAM-1), and inflammatory enzymes(cycloxygenase-2, iNOS). The c-fos component of AP-1 isalso activated in asthmatic airways and often cooperateswith NF-jB in switching on inflammatory genes.133

ANTI-INFLAMMATORY MECHANISMS INASTHMA

Although most emphasis has been placed on inflamma-tory mechanisms, there may be important anti-inflamma-tory mechanisms that may be defective in asthma, resultingin increased inflammatory responses in the airways (Fig.35.8). Endogenous cortisol may be important as a regulatorof the allergic inflammatory response, and nocturnal exacer-bation of asthma may be related to the circadian fall inplasma cortisol. Blockade of endogenous cortisol secretionby metyrapone results in an increase in the late response toallergen in the skin.134 Cortisol is converted to the inactivecortisone by the enzyme 11b-hydroxysteroid dehydrogenasewhich is expressed in airway tissues.135 It is possible that thisenzyme functions abnormally in asthma or may determinethe severity of asthma.


INFLAMMATORYSTIMULI

Allergens, viruses,cytokines

Receptor

Kinases Inactivetranscriptionfactor

mRNA

INFLAMMATORYPROTEINS

Cytokines, enzymes, receptors,adhesion molecules

Activatedtranscription factor(NF-κB, AP-1, STATs)

Coding regionPromoter

Nucleus

Inflammatorygene

P

Fig. 35.7. Transcription factors play a key role in amplifying and perpetuating the inflammatory response in asthma. Transcription factors, includingnuclear factor kappa-B (NF-jB), activator protein-1 (AP-1), and signal transduction-activated transcription factors (STATs), are activated by inflam-matory stimuli and increase the expression of multiple inflammatory genes.

35 Chapter 0935 6/3/02 4:45 pm Page 352

Various cytokines have anti-inflammatory actions.136 IL-1receptor antagonist (IL-1ra) inhibits the binding of IL-1 toits receptors and therefore has anti-inflammatory potentialin asthma. It is reported to be effective in an animal modelof asthma.137 IL-12 and interferon-c (IFN-c) enhance Th1cells and inhibit Th2 cells, and there is some evidence thatIL-12 expression may be impaired in asthma.39 IL-10, whichwas originally described as cytokine synthesis inhibitory fac-tor, inhibits the expression of multiple inflammatorycytokines (TNF-a, IL-1b, GM-CSF) and chemokines, aswell as inflammatory enzymes (iNOS, COX-2).138 It may

produce this widespread anti-inflammatory action byinhibiting NF-jB.139 There is evidence that IL-10 secretionand gene transcription are defective in macrophages andmonocytes from asthmatic patients;140,141 this may lead toenhancement of inflammatory effects in asthma and may bea determinant of asthma severity (Fig. 35.9).

Other mediators may also have anti-inflammatory andimmunosuppressive effects. PGE2 has inhibitory effects onmacrophages, epithelial cells, and eosinophils. ExogenousPGE2 inhibits allergen-induced airway responses, and itsendogenous generation may account for the refractoryperiod after exercise challenge.142 However, it is unlikely thatendogenous PGE2 is important in most asthmatics sincenonselective cycloxygenase inhibitors worsen asthma only ina minority of patients (aspirin-induced asthma). Other lipidmediators may also be anti-inflammatory, including 15-HETE that is produced in high concentration by airwayepithelial cells. 15-HETE and lipoxins may inhibit cysteinyl-leukotriene effects on the airways.143 Lipoxins are known tohave strong anti-inflammatory effects, most likely throughmodulation of the trafficking of key intracellular proinflam-matory intermediates.144,145 The peptide adrenomedullin,which is expressed in high concentrations in lung, hasbronchodilator activity146 and also appears to inhibit thesecretion of cytokines from macrophages.147 Its role inasthma is currently unknown.

Airway and alveolar macrophages have a predominantlysuppressive effect in asthma and inhibit T cell prolifera-tion.148,149 The mechanism of macrophage-inducedimmunosuppression is not yet certain, but PGE2 and IL-10secretion may contribute. There is some evidence that theimmunosuppressive effect of macrophages is reduced inasthmatic patients after allergen challenge in vitro, thusfavoring T cell proliferation.15


INFLAMMATORYMEDIATORSLipid mediators

CytokinesPeptidesOxidants

ANTI-INFLAMMATORY

MEDIATORSIL-10IL-1ra

IFN-γ, IL-12, IL-18PGE2

Fig. 35.8. There may be an imbalance between increased proinflamma-tory mediators and a deficiency in anti-inflammatory mediators.

earlyMacrophage

late

Inflammatory stimuli LPS

NF-κB

Inflammatory proteinsiNOS, COX-2

IL-1β, TNF-α, GM-CSFMIP-1α, RANTES

�

�

�

�

�IL-10

CorticosteroidsTheophylline?PDE4 inhibitors

NF-κB

Fig. 35.9. Interleukin-10 is an anti-inflammatory cytokine that may inhibit the expression of inflammatory mediators from macrophages. IL-10 secre-tion is deficient in macrophages from patients with asthma, resulting in increased release of inflammatory mediators.

35 Chapter 0935 6/3/02 4:46 pm Page 353

GENETIC INFLUENCES

There is now extensive research on the genetics of asthma,although most of this research relates to the genetics ofatopy, which provides little insight into the mechanisms ofasthma.150 Atopy is clearly determined by genetic factorsand several genes appear to be involved, although there aremarked differences between different populations. There isevidence for linkage between markers on chromosome11q13 which may relate to polymorphism of the gene cod-ing for the b-chain of the high-affinity IgE receptor (FceRI),and 5q31, which codes for a cytokine cluster IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF. There are also associationsbetween these linkages and airway hyperresponsiveness,although it is difficult to dissociate changes in airway reac-tivity from atopy. Atopy is the most important risk factor forthe development of asthma; but while understanding thegenetics of atopy will shed light on the nature of allergicinflammation, it may not be very informative in under-standing asthma. It is likely that environmental factors(viral/bacterial infections, allergen exposure, diet) may bemore important in determining whether an atopic individ-ual becomes an asthmatic patient.

However, once asthma is established, genetic factors maybe important in determining the severity of the disease andits response to therapy (Fig. 35.10). Polymorphisms havebeen described in many genes involved in the inflammatoryprocess and may occur in coding and promoter regions,resulting in increased production of inflammatory media-tors, such as cytokines, for example. It is likely that a com-bination of multiple single-nucleotide polymorphisms(SNP) will help predict the natural history and outcome ofasthma, but this idea has not yet been reduced to practice.

An area of importance is the relationship between clinicalresponses to anti-asthma treatments and genotype at variousdrug targets. For example there are known to be a numberof SNPs in the b2-adrenoceptor gene that result in structuralchanges in the b2-receptor structure associated with func-tional changes in isolated cell systems.151 These are relatedto the acute response to bronchodilator aerosols acting viathis receptor,152,153 and with deleterious effects of chronicuse of salbutamol.154,155 Similarly, there are genetically basedfunctional variants in the regulation of the ALOX-5gene156–158 which modify the clinical response to these treat-ments.159 Thus genetics may have its greatest impact onunderstanding the variance in asthma treatment responses.

It is currently unclear why some patients develop severeasthma while others remain with mild disease throughouttheir lives. It is likely that genetic factors are important. Anexample of genetic polymorphism that is associated withasthma severity is the haplotypes of the IL-10 gene pro-moter that are linked to different expression of the IL-10gene. Haplotypes that are associated with increased IL-10production are significantly more commonly associated withmild asthma, whereas haplotypes associated with decreasedproduction are more commonly associated with severeasthma.160 Another polymorphism of significance to thephenotype of severe asthma is the SNP in the promoter ofthe IL-4 gene.161 When present this SNP results in thecreation of a binding site for NFAT gene; this SNP has beenassociated with lower FEV1 values among patients with adiagnosis of asthma.

UNANSWERED QUESTIONS

Although our understanding of asthma has advanced veryrapidly in recent years and this has led to a fundamentalchange in the approach to therapy, many important ques-tions remain unanswered.162

Why is the prevalence of asthma increasing throughout the worldas a consequence of Westernization?It is not clear what environmental factors are most impor-tant for the increase in atopic diseases, but it is likely thatseveral factors are operating together. These factors includediet (reduced intake of antioxidants, reduced unsaturatedfats), lack of early childhood infections (with consequenttendency to develop Th2-driven responses), greater expo-sure to allergens in the home (tight housing, mattresses,central heating providing more favorable environment),cigarette smoking (pregnancy and early childhood expo-sure) and possibly air pollution due to road traffic.

Why does asthma once established become chronic in someindividuals but remain intermittent and episodic in others?For example, occupational asthma due to chemical sensi-tizers, such as toluene diisocyanate, may remit if the patientis removed from exposure to the sensitizer within 6 monthsof development of asthma symptoms, whereas longer


AtopyAHR

GENES AND ASTHMA

ASTHMA

Mild Severe

EnvironmentAllergensInfectionsDiet, etc.Pollutants?

Genes

GenesEnvironment

Fig. 35.10. There is an interaction between genetic and environmentalfactors in asthma.

35 Chapter 0935 6/3/02 4:46 pm Page 354

exposure is often associated with persistent asthma evenwhen avoidance of exposure is complete.163 This suggeststhat once inflammation is established it may continue inde-pendently of a causal mechanism. In contrast, numerouspatients with asthma due to environmental exposures, suchas dust mites, can become asthma-free when removed fromthe exposure.

Are there different types of asthma, each characterized by a com-mon genetic background with its attendant immunological andinflammatory response?Intrinsic asthma, where there is no identifiable atopy, looksvery similar to allergic asthma clinically and immunocyto-chemically, yet there are likely to be immunological differ-ences. Can we develop genetic or biochemical criteria whichwould allow identification of phenotypically uniform patientcohorts?

How does inflammation of the airways translate into clinicalsymptoms of asthma?Airway thickening, as a consequence of the inflammatoryresponse, may contribute to increased responsiveness tospasmogens.164,165 However, there is no obvious relationshipbetween the inflammatory response in airways and asthmaseverity; patients with mild asthma may have a similareosinophil response to patients with severe asthma, sug-gesting that there are other factors that determine clinicalseverity. The nature of these “factors” remains elusive, butwe must identify them if we are to make true scientificprogress.

How important are genetic factors (genetic polymorphisms) indetermining the phenotype of asthma?Disease is of differing severity and varying responsiveness tosteroids, b2-agonists and other therapies. By determiningthe profile of genetic polymorphisms in an individualpatient, using novel gene-chip technology, it may be possibleto predict who is at risk for asthma, to predict the severity ofasthma, or to predict the response to treatment.

Are asthma and atopy causally related or just closely linked?Much of our understanding of asthma derives from study ofmodels of allergy. Although these models are of great valuein defining the pathobiology of asthma, how closely will theyrelate to the human disease?

REFERENCES

1. Bousquet J, Jeffery PK, Busse WW, Johnson M,Vignola AM. Frombronchoconstriction to airways inflammation and remodeling.Am. J. Respir. Crit. Care Med. 2000; 161:1720–45.

2. Dunnill MS.The pathology of asthma, with special reference to thechanges in the bronchial vasculature. J. Clin. Pathol. 1960;13:27–33.

3. Hamid Q, Song YL, Kotsimbos TC et al. Inflammation of small air-ways in asthma. J. Allergy Clin. Immunol. 1997; 100:44–51.

4. Martin RJ. Small airway and alveolar tissue changes in nocturnalasthma. Am. J. Respir. Crit. Care Med. 1998; 157:S188–90.

5. Laitinen LA, Laitinen A, Altraja A et al. Bronchial biopsy findingsin intermittent or “early” asthma. J.Allergy Clin. Immunol. 1996;98(5 Part 2):S3–6.

6. Jeffery PK. Structural and inflammatory changes in COPD: a com-parison with asthma. Thorax 1998; 53:129–36.

7. Barnes PJ. Chronic obstructive pulmonary disease. N. Engl. J. Med.2000; 343:269–80.

8. Ammit AJ, Bekir SS, Johnson PRA et al. Mast cell numbers areincreased in the smooth muscle of human sensitized isolatedbronchi. Am. J. Respir. Crit.Care Med. 1997; 155:1123–9.

9. Bentley AM, Hamid Q, Robinson DS et al. Prednisolone treatmentin asthma: reduction in the numbers of eosinophils, T cells,tryptase-only positive mast cells, and modulation of IL-4, IL-5,and interferon-gamma cytokine gene expression within thebronchial mucosa. Am. J. Respir. Crit. Care Med. 1996;153:551–6.

10. Foresi A, Leone C, Pelucchi A. Eosinophils, mast cells, andbasophils in induced sputum from patients with seasonal aller-gic rhinitis and perennial asthma: relationship to methacholineresponsiveness. J. Allerg. Clin. Immunol. 1997; 100:58–64.

11. Akers IA, Parsons M, Hill MR et al. Mast cell tryptase stimulateshuman lung fibroblast proliferation via protease-activated recep-tor-2. Am. J. Physiol. 2000; 278:L193–201.

12. Costa JJ,Weller PF, Galli SJ.The cells of the allergic response: mastcells, basophils, and eosinophils. JAMA 1997; 278:1815–22.

13. Milgrom H, Fick RB, Su JQ et al.Treatment of allergic asthma withmonoclonal anti-IgE antibody. N. Engl. J. Med. 1999;341:1966–73.

14. Lee TH, Lane SJ. The role of macrophages in the mechanisms ofairway inflammation in asthma. Am. Rev. Respir. Dis. 1992;145:S27–30.

15. Spiteri MA, Knight RA, Jeremy JY et al. Alveolar macrophage-induced suppression of peripheral blood mononuclear cellresponsiveness is reversed by in-vitro allergen exposure inbronchial asthma. Eur. Respir. J. 1994; 7:1431–8.

16. Holt PG, McMenamin C. Defence against allergic sensitization inthe healthy lung: the role of inhalation tolerance. Clin. Exp.Allergy 1989; 19:255–62.

17. Holt PG, Stumbles PA. Regulation of immunologic homeostasis inperipheral tissues by dendritic cells: the respiratory tract as aparadigm. J. Allergy Clin. Immunol. 2000; 105:421–9.

18. Stumbles PA,Thomas JA, Pimm CL et al. Resting respiratory tractdendritic cells preferentially stimulate T helper cell type 2 (Th2)responses and require obligatory cytokine signals for inductionof Th1 immunity. J. Exp. Med. 1998; 188:2019–31.

19. Gleich GJ. Mechanisms of eosinophil associated inflammation. J.Allergy Clin. Immunol. 2000; 105:651–63.

20. Wegner CD, Gundel RH, Reilly P et al. Intercellular adhesionmolecule-1 (ICAM-1) in the pathogenesis of asthma. Science1990; 247:456–9.

21. Pilewski JM, Albelda SM. Cell adhesion molecules in asthma:homing, activation, and airway remodeling. Am. J. Respir. CellMol. Biol. 1995; 12:1–3.

22. Lamas AM, Mulroney CM, Schleimer RP. Studies on the adhesiveinteraction between purified human eosinophils and culturedvascular endothelial cells. J. Immunol. 1988; 140:1500–5.

23. Laitinen LA, Laitinen A, Haahtela T et al. Leukotriene-E4 andgranulocytic infiltration into asthmatic airways. Lancet 1993;341:989–90.

24. Chanez P, Dent G,Yukawa T, Barnes PJ, Chung KF. Generation ofoxygen free radicals from blood eosinophils from asthmapatients after stimulation with PAF or phorbol ester. Eur. Respir.J. 1990; 3:1002–7.

25. Evans DJ, Lindsay MA, O’Connor BJ, Barnes PJ. Priming of cir-culating human eosinophils following late response to allergenchallenge. Eur. Respir. J. 1996; 9:703–8.

26. Berkman N, Krishnan VL, Gilbey T et al. Expression of RANTESmRNA and protein in airways of patients with mild asthma.Am.J. Respir. Crit. Care Med. 1996; 154:1804–11.


35 Chapter 0935 6/3/02 4:46 pm Page 355

27. Ponath PD, Qin S, Ringler DJ et al. Cloning of the humaneosinophil chemoattractant, eotaxin. Expression, receptorbinding, and functional properties suggest a mechanism for theselective recruitment of eosinophils. J. Clin. Invest. 1996;97:604–12.

28. Collins PD, Marleau S, Griffithsjohnson DA, Jose PJ, Williams TJ.Cooperation between interleukin-5 and the chemokine eotaxinto induce eosinophil accumulation in vivo. J. Exp. Med. 1995;182:1169–74.

29. Park CS, Choi YS, Ki SY et al. Granulocyte macrophage colony-stimulating factor is the main cytokine enhancing survival ofeosinophils in asthmatic airways. Eur. Respir. J. 1998; 12:872–8.

30. Leckie MJ, ten Brincke A, Khan J et al. Effects of an interleukin-5blocking monoclonal antibody on eosinophils, airway hyperre-sponsiveness and the late asthmatic response. Lancet 2000;356:2144–8.

31. Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel JA. Mecha-nisms of bronchial hyperreactivity in normal subjects afterupper respiratory tract infection. Am. Rev. Respir. Dis. 1976;113:131–9.

32. Wenzel SE, Szefler SJ, Leung DY et al. Bronchoscopic evaluation ofsevere asthma: persistent inflammation associated with highdose glucocorticoids. Am. J. Respir. Crit. Care Med. 1997;156:737–43.

33. Sur S, Crotty TB, Kephart GM et al. Sudden-onset fatal asthma: adistinct entity with few eosinophils and relatively moreneutrophils in the airway submucosa. Am. Rev. Respir. Dis. 1993;148:713–19.

34. Mosmann TR, Sad S. The expanding universe of T-cell subsets:Th1, Th2 and more. Immunol.Today 1996; 17:138–46.

35. Prescott SL, Macaubas C, Smallacombe T et al. Development ofallergen-specific T-cell memory in atopic and normal children.Lancet 1999; 353:196–200.

36. Holt PG, Sly PD. Prevention of adult asthma by early interventionduring childhood: potential value of new generationimmunomodulatory drugs. Thorax 2000; 55:700–3.

37. Ball TM, Castro-Rodriquez JA, Griffith KA et al. Siblings, day-careattendance, and the risk of asthma and wheezing during child-hood. N. Engl. J. Med. 2000; 343:538–43.

38. Christiansen SC. Day care, siblings, and asthma: please, sneeze onmy child. N. Engl. J. Med. 2000; 343:574–5.

39. Naseer T, Minshall EM, Leung DY et al. Expression of IL-12 andIL-13 mRNA in asthma and their modulation in response tosteroid therapy. Am. J. Respir. Crit. Care Med. 1997; 155:845–51.

40. Wills-Karp M, Luyimbazi J, Xu X et al. Interleukin-13: centralmediator of allergic asthma. Science 1998; 282:2258–61.

41. Grunig G,Warnock M,Wakil AE et al. Requirement for IL-13 inde-pendently of IL-4 in experimental asthma. Science 1998;282:2261–3.

42. Zhou Z, Homer RJ,Wang ZD et al. Pulmonary expression of inter-leukin-13 causes inflammation, mucus hypersecretion, sub-epithelial fibrosis, physiologic abnormalities, and eotaxinproduction. J. Clin. Invest. 1999; 103:779–88.

43. Macfarlane AJ, Kon OM, Smith SJ et al. Basophils, eosinophils,and mast cells in atopic and nonatopic asthma and in late-phaseallergic reactions in the lung and skin. J. Allergy Clin. Immunol.2000; 105:99–107.

44. Levine SJ. Bronchial epithelial cell–cytokine interactions in airwayinflammation. J. Invest. Med. 1995; 43:241–9.

45. Devalia JL, Davies RJ. Airway epithelial cells and mediators ofinflammation. Respir. Med. 1993; 87:405–8.

46. Saunders MA, Mitchell JA, Seldon PM et al. Release of granulo-cyte-macrophage colony stimulating factor by human culturedairway smooth muscle cells: suppression by dexamethasone. Br.J. Pharmacol. 1997; 120:545–6.

47. Barnes PJ, Chung KF, Page CP. Inflammatory mediators andasthma. Pharmacol. Rev. 1988; 40:49–84.

48. Holgate ST. The cellular and mediator basis of asthma in relationto natural history. Lancet 1997; 350:5–9.

49. Obyrne PM, Israel E, Drazen JM. Antileukotrienes in the treatmentof asthma. Ann. Intern. Med. 1997; 127:472–80.

50. Drazen JM, Israel E, O’Byrne PM.Treatment of asthma with drugsmodifying the leukotriene pathway. N. Engl. J. Med. 1999;340:197–206.

51. Stene DO, Murphy RC. Metabolism of leukotriene E4 in isolatedrat hepatocytes: identification of beta-oxidation products ofsulfidopeptide leukotrienes. J. Biol. Chem. 1988; 263:2773–8.

52. Leff JA, Busse WW, Pearlman D et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma andexercise-induced bronchoconstriction. N. Engl. J. Med. 1998;339:147–52.

53. Adelroth E, Inman MD, Summers E et al. Prolonged protectionagainst exercise-induced bronchoconstriction by the leukotrieneD4-receptor antagonist cinalukast. J. Allergy Clin. Immunol.1997; 99:210–15.

54. Taylor IK, O’Shaughnessy KM, Fuller RW, Dollery CT. Effect ofcysteinyl-leukotriene receptor antagonist ICI 204.219 onallergen-induced bronchoconstriction and airway hyperreactivityin atopic subjects. Lancet 1991; 337:690–4.

55. Hamilton A, Faiferman I, Stober P et al. Pranlukast, a cysteinylleukotriene receptor antagonist, attenuates allergen-inducedearly- and late-phase bronchoconstriction and airway hyperre-sponsiveness in asthmatic subjects. J. Allergy Clin. Immunol.1998; 102:177–83.

56. Roquet A, Dahlen B, Kumlin M et al. Combined antagonism ofleukotrienes and histamine produces predominant inhibition ofallergen-induced early and late phase airway obstruction inasthmatics. Am. J. Respir. Crit. Care Med. 1997; 155:1856–63.

57. Dermarkarian RM, Israel E, Rosenberg MA et al. The effect ofSCH-37370, a dual platelet activating factor (PAF) and hista-mine antagonist, on the bronchoconstriction induced in asth-matics by cold, dry air isocapnic hyperventilation (ISH). Am.Rev. Respir. Dis. 1991; 143:A812.

58. Freitag A, Watson RM, Matsos G, Eastwood C, Obyrne PM.Effect of a platelet activating factor antagonist, WEB-2086,on allergen-induced asthmatic responses. Thorax 1993;48:594–8.

59. Spence DP, Johnston SL, Calverley PM et al. The effect of theorally active platelet-activating factor antagonist WEB 2086 inthe treatment of asthma. Am. J. Respir. Crit. Care Med. 1994;149:1142–8.

60. Kuitert LM, Angus RM, Barnes NC et al. Effect of a novel potentplatelet-activating factor antagonist, modipafant, in clinicalasthma. Am. J. Respir. Crit. Care Med. 1995; 151:1331–5.

61. Stafforini DM, Satoh K, Atkinson DL et al. Platelet-activating fac-tor acetylhydrolase deficiency: a missense mutation near theactive site of an anti-inflammatory phospholipase. J. Clin. Invest.1996; 97:2784–91.

62. Stafforini DM, Numao T, Tsodikov A et al. Deficiency of platelet-activating factor acetylhydrolase is a severity factor for asthma.J. Clin. Invest. 1999; 103:989–97.

63. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999;54:825–57.

64. Barnes PJ. Cytokines as mediators of chronic asthma. Am. J. Respir.Crit. Care Med. 1994; 150:S42–9.

65. Hamid Q, Azzawi M, Ying S et al. Expression of messenger RNAfor interleukin-5 in mucosal bronchial biopsies from asthma.J. Clin. Invest. 1991; 87:1541–6.

66. Levitt RC, McLane MP, Macdonald D et al. IL-9 pathway inasthma: new therapeutic targets for allergic inflammatory disor-ders. J. Allergy Clin. Immunol. 1999; 103:S485–91.

67. Holroyd KJ, Martinati LC, Trabetti E et al. Asthma and bronchialhyperresponsiveness linked to the XY long arm pseudoautoso-mal region. Genomics 1998; 52:233–5.

68. McLane MP, Haczku A,Vanderijn M et al. Interleukin-9 promotesallergen-induced eosinophilic inflammation and airway hyper-responsiveness in transgenic mice. Am. J. Respir. Cell Mol. Biol.1998; 19:713–20.


35 Chapter 0935 6/3/02 4:46 pm Page 356

69. Kips JC,Tavernier JH, Joos GF, Peleman RA, Pauwels RA. Review:The potential role of tumour necrosis factor-a in asthma. Clin.Exp. Allergy 1993; 23:247–50.

70. Thomas PS, Yates DH, Barnes PJ. Tumor necrosis factor-alphaincreases airway responsiveness and sputum neutrophilia innormal human subjects. Am. J. Respir. Crit. Care Med. 1995;152:76–80.

71. Humbles AA, Lu B, Nilsson CA et al. A role for the C3a anaphyla-toxin receptor in the effector phase of asthma. Nature 2000;406:998–1001.

72. Karp CL, Grupe A, Schadt E et al. Identification of complementfactor 5 as a susceptibility locus for experimental allergicasthma. Nat. Immunol. 2000; 1:221–6.

73. Montuschi P,Corradi M,Ciabattoni G et al.Increased 8-isoprostane,a marker of oxidative stress, in exhaled condensate of asthmapatients. Am. J. Respir. Crit. Care Med. 1999; 160:216–20.

74. Paredi P, Leak D, Ward S et al. Increased exhaled ethane in theexhaled air of asthmatic patients. Am. J. Respir. Crit. Care Med.1999; 159:A97.

75. Barnes PJ. Endothelins and pulmonary diseases. J. Appl. Physiol.1994; 77:1051–9.

76. Chalmers GW, Thomson L, Macleod KJ et al. Endothelin-1 levelsin induced sputum samples from asthmatic and normal sub-jects. Thorax 1997; 52:625–7.

77. Redington AE, Springall DR, Ghatei MA et al. Airway endothelinlevels in asthma: influence of endobronchial allergen challengeand maintenance corticosteroid therapy. Eur. Respir. J. 1997;10:1026–32.

78. Redington AE, Springall DR, Meng QH et al. Immunoreactiveendothelin in bronchial biopsy specimens: increased expressionin asthma and modulation by corticosteroid therapy. J. AllergyClin. Immunol. 1997; 100:544–52.

79. Barnes PJ. Nitric oxide and airway disease. Ann. Med. 1995;27:389–93.

80. Silkoff PE, Sylvester JT, Zamel N, Permutt S. Airway nitric oxidediffusion in asthma: role in pulmonary function and bronchialresponsiveness. Am. J. Respir. Crit. Care Med. 2000;161:1218–28.

81. Gustafsson LE, Leone AM, Persson MG,Wiklund NP, Moncada S.Endogenous nitric oxide is present in the exhaled air of rabbits,guinea pigs and humans. Biochem. Biophys. Res. Commun. 1991;181:852–7.

82. Kharitonov SA,Yates D, Robbins RA et al. Increased nitric oxide inexhaled air of asthmatic patients. Lancet 1994; 343:133–5.

83. Massaro A, Mehta S, Lilly CM et al. Elevated nitric oxide concen-trations on isolated lower airway gas of asthmatic subjects. Am.J. Respir. Crit. Care Med. 1996; 153:1510–14.

84. Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Corre-lation between exhaled nitric oxide, sputum eosinophils, andmethacholine responsiveness in patients with mild asthma.Thorax 1998; 53:91–5.

85. Lim S, Jatakanon A, Meah S et al. Relationship between exhalednitric oxide and mucosal eosinophilic inflammation in mild tomoderately severe asthma. Thorax 2000; 55:184–8.

86. Hunt JF, Fang KZ, Malik R et al. Endogenous airway acidification:implications for asthma pathophysiology. Am. J. Respir. Crit. CareMed. 2000; 161:694–9.

87. Saleh D, Ernst P, Lim S, Barnes PJ, Giaid A. Increased formationof the potent oxidant peroxynitrite in the airways of asthmaticpatients is associated with induction of nitric oxide synthase:effect of inhaled glucocorticoid. FASEB J. 1998; 12:929–37.

88. Jeffery PK,Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchialbiopsies in asthma: an ultrastructural, quantitative study andcorrelation with hyperreactivity. Am. Rev. Respir. Dis. 1989;140:1745–53.

89. Chetta A, Foresi A, Del Donno M et al. Bronchial responsivenessto distilled water and methacholine and its relationship toinflammation and remodeling of the airways in asthma. Am.J.Respir. Crit. Care Med. 1996; 153:910–17.

90. Chetta A, Foresi A, Del Donno M et al. Airways remodeling is adistinctive feature of asthma and is related to severity of disease.Chest 1997; 111:852–7.

91. Ressler B, Lee RT, Randell SH, Drazen JM, Kamm RD. Molecu-lar responses of rat tracheal epithelial cells to transmembranepressure. Am. J. Physiol. 2000; 278:L1264–72.

92. Kips JC, Pauwels RA. Airway wall remodelling: does it occur andwhat does it mean? Clin. Exp. Allergy 1999; 29:1457–66.

93. Fish JE, Peters SP. Airway remodeling and persistent airwayobstruction in asthma. J. Allergy Clin. Immunol. 2000; 105:185.

94. Bai TR, Mak JC, Barnes PJ. A comparison of beta-adrenergicreceptors and in-vitro relaxant responses to isoproterenol inasthmatic airway smooth muscle. Am. J. Respir. Cell Mol. Biol.1992; 6:647–51.

95. Laporte JD, Moore PE, Panettieri RA et al. Prostanoids mediateIL-1beta-induced beta-adrenergic hyporesponsiveness inhuman airway smooth muscle cells. Am. J. Physiol. 1998;275:L491–501.

96. Moore PE, Laporte JD, Gonzalez S et al. Glucocorticoids ablateIL-1b-induced b-adrenergic hyporesponsiveness in human air-way smooth muscle cells. Am. J. Physiol. 1999; 277:L932–42.

97. Grandordy BM, Mak JCW, Barnes PJ. Modulation of airwaysmooth muscle beta-adrenoceptor function by a muscarinicagonist. Life Sci. 1994; 54:185–91.

98. Koto H, Mak JC, Haddad EB et al. Mechanisms of impairedb-adrenoceptor-induced airway relaxation by interleukin-1betain vivo in the rat. J. Clin. Invest. 1996; 98:1780–7.

99. Ebina M,Yaegashi H, Chiba R et al. Hyperreactive site in the air-way tree of asthmatic patients revealed by thickening ofbronchial muscles: a morphometric study. Am. Rev. Respir. Dis.1990; 141:1327–32.

100. Kumar SD, Emery MJ, Atkins ND, Danta I, Wanner A. Airwaymucosal blood flow in bronchial asthma. Am. J. Respir. Crit. CareMed. 1998; 158:153–6.

101. McFadden ER. Hypothesis: exercise-induced asthma as a vascularphenomenon. Lancet 1990; 335:880–3.

102. Uematsu M, Ohara Y, Navas JP et al. Regulation of endothelial cellnitric oxide synthase mRNA expression by shear stress. Am. J.Physiol. 1995; 38:C1371–8.

103. Malek AM, Jiang LW, Lee I et al. Induction of nitric oxidesynthase mRNA by shear stress requires intracellular calciumand G-protein signals and is modulated by PI 3 kinase. Biochem.Biophys. Res. Commun. 1999; 254:231–42.

104. Kuwano K, Bosken CH, Paré PD et al. Small airways dimensionsin asthma and in chronic obstructive pulmonary disease. Am.Rev. Respir. Dis. 1993; 148:1220–5.

105. Wilson J. The bronchial microcirculation in asthma. Clin. Exp.Allergy 2000; 30(Suppl. 1):51–3.

106. Persson CG. Plasma exudation and asthma. Lung 1988;166:1–23.

107. Chung KF, Rogers DF, Barnes PJ, Evans TW. The role ofincreased airway microvascular permeability and plasmaexudation in asthma. Eur. Respir. J. 1990; 3:329–37.

108. Persson CGA, Andersson M, Greiff L et al. Airway permeability.Clin. Exp. Allergy 1995; 25:807–14.

109. Yager D, Martins MA, Feldman H, Kamm RD, Drazen JM. Acutehistamine-induced flux of airway liquid: role of neuropeptides.J. Appl. Physiol. 1996; 80:1285–95.

110. Jayawickreme SP, Gray T, Nettesheim P, Eling T. Regulation of 15-lipoxygenase expression and mucus secretion by IL-4 in humanbronchial epithelial cells. Am. J. Physiol. 1999; 20:L596–603.

111. Barnes PJ. Is asthma a nervous disease? The Parker B. FrancisLecture. Chest 1995; 107:119S–25S.

112. Lou YP, Francocereceda A, Lundberg JM. Variable a2-adrenoceptor-mediated inhibition of bronchoconstriction andpeptide release upon activation of pulmonary afferents. Eur. J.Pharmacol. 1992; 210:173–81.

113. Barnes PJ, Baraniuk JN, Belvisi MG. Neuropeptides in the respi-ratory tract: I. Am. Rev. Respir. Dis. 1991; 144:1187–98.

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114. Joos GF, Germonpre PR, Pauwels R. Role of tachykinins inasthma. Allergy 2000; 55:321–37.

115. Canning BJ, Undem BJ. Evidence that antidromically stimulatedvagal afferents activate inhibitory neurones innervating guinea-pig trachealis. J. Physiol. London 1994; 480:613–25.

116. Barnes PJ. Modulation of neurotransmission in airways. Physiol.Rev. 1992; 72:699–729.

117. Braun A, Lommatzsch M, Lewin GR, Virchow JC, Renz H.Neurotrophins: a link between airway inflammation and airwaysmooth muscle contractility in asthma? Int. Arch. AllergyImmunol. 1999; 118:163–5.

118. Lammers JW, Barnes PJ, Chung KF. Nonadrenergic, noncholin-ergic airway inhibitory nerves. Eur. Respir. J. 1992; 5:239–46.

119. Ollerenshaw S, Jarvis D, Woolcock A, Sullivan C, Scheibner T.Absence of immunoreactive vasoactive intestinal polypeptide intissue from the lungs of patients with asthma. N. Engl. J. Med.1989; 320:1244–8.

120. Belvisi MG, Stretton CD,Yacoub M, Barnes PJ. Nitric oxide is theendogenous neurotransmitter of bronchodilator nerves inhumans. Eur. J. Pharmacol. 1992; 210:221–2.

121. Lilly CM, Martins MA, Drazen JM. Peptidase modulation ofvasoactive intestinal peptide pulmonary relaxation in trachealsuperfused guinea pig lungs. J. Clin. Invest. 1993; 91:235–43.

122. Barnes PJ. Sensory nerves, neuropeptides, and asthma. Ann. NYAcad. Sci. 1991; 629:359–70.

123. Ollerenshaw SL, Jarvis D, Sullivan CE, Woolcock AJ. SubstanceP immunoreactive nerves in airways from asthmatics andnonasthmatics. Eur. Respir. J. 1991; 4:673–82.

124. Howarth PH, Springall DR, Redington AE et al. Neuropeptide-containing nerves in endobronchial biopsies from asthmatic andnonasthmatic subjects. Am. J. Respir. Cell Mol. Biol. 1995;13:288–96.

125. Nadel JA. Neutral endopeptidase modulates neurogenic inflam-mation. Eur. Respir. J. 1991; 4:745–54.

126. Adcock IM,Peters M,Gelder C et al. Increased tachykinin receptorgene expression in asthmatic lung and its modulation by steroids.J. Mol. Endocrinol. 1993; 11:1–7.

127. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year fol-low-up study of ventilatory function in adults with asthma. N.Engl. J. Med. 1998; 339:1194–200.

128. Brown PJ, Greville HW, Finucane KE. Asthma and irreversibleairflow obstruction. Thorax 1984; 39:131–6.

129. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur.Respir. J. 1998; 12:221–34.

130. Barnes PJ, Adcock IM. Transcription factors. Clin. Exp. Allergy1995; 25(Suppl. 2):46–9.

131. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcrip-tion factor in chronic inflammatory diseases. N. Engl. J. Med.1997; 336:1066–71.

132. Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF.Activation and localization of transcription factor, nuclearfactor-kappa B, in asthma. Am. J. Respir. Crit. Care Med. 1998;158:1585–92.

133. Demoly P, Basset-Seguin N, Chanez P et al. c-fos proto-oncogeneexpression in bronchial biopsies of asthmatics. Am. J. Respir. CellMol. Biol. 1992; 7:128–33.

134. Herrscher RF, Kasper C, Sullivan TJ. Endogenous cortisol regu-lates immunoglobulin E-dependent late phase reactions. J. Clin.Invest. 1992; 90:596–603.

135. Schleimer RP. Potential regulation of inflammation in the lung bylocal metabolism of hydrocortisone. Am. J. Respir. Cell Mol. Biol.1991; 4:166–73.

136. Barnes PJ, Lim S. Inhibitory cytokines in asthma. Mol. Med.Today1998; 4:452–8.

137. Selig W, Tocker J. Effect of interleukin-1 receptor antagonist onantigen-induced pulmonary responses in guinea pigs. Eur. J.Pharmacol. 1992; 213:331–6.

138. Ho AS, Moore KW. Interleukin-10 and its receptor. Therap.Immunol. 1994; 1:173–85.

139. Wang P,Wu P, Siegel MI, Egan RW, Billah MM. Interleukin (IL)-10 inhibits nuclear factor kappa B (NF-jB) activation in humanmonocytes. IL-10 and IL-4 suppress cytokine synthesis bydifferent mechanisms. J. Biol. Chem. 1995; 270:9558–63.

140. Borish L, Aarons A, Rumbyrt J et al. Interleukin-10 regulation innormal subjects and patients with asthma. J. Allergy Clin.Immunol. 1996; 97:1288–96.

141. John M, Lim S, Seybold J et al. Inhaled corticosteroids increaseinterleukin-10 but reduce macrophage inflammatory protein-1a, granulocyte–macrophage colony-stimulating factor, andinterferon-c release from alveolar macrophages in asthma. Am.J. Respir. Crit. Care Med. 1998; 157:256–62.

142. Pavord ID, Tattersfield AE. Bronchoprotective role for endoge-nous prostaglandin E2. Lancet 1995; 345:436–8.

143. Lee TH. Lipoxin A4: a novel anti-inflammatory molecule? Thorax1995; 50:111–12.

144. Levy BD, Fokin VV, Clark JM et al. Polyisoprenyl phosphate(PIPP) signaling regulates phospholipase D activity: a “stop”signaling switch for aspirin-triggered lipoxin A4. FASEB J.1999; 13:903–11.

145. Levy BD, Petasis NA, Serhan CN. Polyisoprenyl phosphates inintracellular signalling. Nature 1997; 389:985–90.

146. Kanazawa H, Kurihara N, Hirata K et al. Adrenomedullin, anewly discovered hypotensive peptide, is a potent bronchodila-tor. Biochem. Biophys. Res. Commun. 1994; 205:251–4.

147. Kamoi H, Kanazawa H, Hirata K et al. Adrenomedullin inhibitsthe secretion of cytokine-induced neutrophil chemoattractant, amember of the interleukin-8 family, from rat alveolarmacrophages. Biochem. Biophys. Res. Commun. 1995;211:1031–5.

148. Holt PG. Regulation of antigen-presenting cell function(s) in lungand airway tissues. Eur. Respir. J. 1993; 6:120–9.

149. Upham JW, Strickland DH, Bilyk N, Robinson BW, Holt PG.Alveolar macrophages from humans and rodents selectivelyinhibit T-cell proliferation but permit T-cell activation andcytokine secretion. Immunology 1995; 84:142–7.

150. Sandford A, Weir T, Paré P. The genetics of asthma. Am. J. Respir.Crit. Care Med. 1996; 153:1749–65.

151. Liggett SB. Polymorphisms of the beta(2)-adrenergic receptorand asthma. Am. J. Respir. Crit. Care Med. 1997; 156:S156–62.

152. Martinez FD, Graves PE, Baldini M, Solomon S, EricksonR. Association between genetic polymorphisms of the b2-adrenoceptor and response to albuterol in children withand without a history of wheezing. J. Clin. Invest. 1997;100:3184–8.

153. Hall IP,Wheatley A, Christie G et al. Association of CCR5 del 32with reduced risk of asthma. Lancet 1999; 354:1264–5.

154. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the beta(2)-adrenoceptor and the response to long-term b2-agonist therapyin asthma. Eur. Resp. J. 1998; 11:589–93.

155. Israel E, Drazen JM, Boushey HA et al. Effect of polymorphismsof the b2-adrenergic receptor on the response to regular use ofalbuterol in asthma. Am. J. Respir. Crit. Care Med. 2000; 162:75–80.

156. In KH, Asano K, Beier D et al. Naturally occurring mutations inthe human 5-lipoxygenase gene promoter that modifytranscription factor binding and reporter gene transcription. J.Clin. Invest. 1997; 99:1130–7.

157. Silverman ES, Du J, Desanctis GT et al. Egr-1 and Sp1 interactfunctionally with the 5-lipoxygenase promoter and its naturallyoccurring mutants. Am. J. Respir. Cell Molec. Biol. 1998;19:316–23.

158. Silverman ES, Du J, Williams AJ et al. cAMP-response-element-binding protein (CBP) and p300 are transcriptional co-activators of early growth response factor-1 (Egr-1). Biochem. J.1998; 336:183–9.

159. Drazen JM, Yandava C, Dube L et al. Pharmacogenetic associa-tion between ALOX5 promoter genotype and the response toanti-asthma treatment. Nature Gen. 1999; 22:170–2.

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160. Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated withlow interleukin-10 production in patients with severe asthma.Lancet 1998; 352:113.

161. Burchard EG, Silverman EK, Rosenwasser LJ et al. Associationbetween a sequence variant in the IL-4 gene promoter andFEV1 in asthma. Am. J. Respir. Crit. Care Med. 1999;160:919–22.

162. Woolcock AJ, Barnes PJ. Asthma: the important questions 3. Am.J. Respir. Crit. Care Med. 2000; 161:S157–230.

163. Chan-Yeung M, Malo JL. Occupational asthma. N. Engl. J. Med.1995; 333:107–12.

164. Paré PD, Bai TR.The consequences of chronic allergic inflamma-tion. Thorax 1995; 50:328–32.

165. Shore SA, Laporte J, Hall IP, Hardy E, Panettieri RAJ. Effect ofIL-1 beta on responses of cultured human airway smoothmuscle cells to bronchodilator agonists. Am. J. Respir. Cell Mol.Biol. 1997; 16:702–12.

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Pathophysiology of Asthma

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