5
Mechanisms of asthma Chris Corrigan Abstract Asthma is a syndrome of variable airflow obstruction. It is characterized pathologically by bronchial inflammation and remodelling changes, phys- iologically by bronchial hyperresponsiveness, and clinically by cough, chest tightness and wheeze. Cytokines secreted by CD4þ Th2 type T cells play a major role in coordinating asthmatic bronchial inflammation, while other effector cells, such as myofibroblasts, epithelial cells, smooth muscle cells and endothelial cells (activated partly by Th2 type cytokines and partly by other mediators), play an intermediary role in airways damage and remodelling. Although the pathological changes in the airways in association with asthma are now well described, there is a gap in our understanding of precisely how these changes cause clinical symptoms. A key aetiological trigger factor for asthma is exposure to environmental antigens, in particular inhaled allergens, including occupa- tional allergens and infectious agents, which are probably a major drive to T cell activation in asthma. Genetic factors governing the production of T cell cytokines and their actions on target cells, as well as variability in the structure and development of the mesenchymal elements of the bron- chial mucosa influence the risk of developing asthma. Many other envi- ronmental agents exacerbate asthma, but the evidence that they cause disease is much less clear. Keywords Asthma; atopy; cytokine; eosinophil; pathogenesis; remod- elling; T cell Clinical pathology The diagnosis of asthma is made on the basis of typical symp- toms and abnormalities in lung function. The key clinical features of asthma include: Variable airways obstruction: airways obstruction in asthma, as measured by spirometry, may vary spontaneously from none to severe in the course of hours to minutes, and improves after suitable therapy. Obstruction, particularly of the smaller airways, in asthmatics causes shortness of breath, impaired exercise tolerance, tightness in the chest that may be perceived as wheeze, and chest hyperinflation (small airways obstruction prevents complete emptying of the alveoli, causing gas trapping). Non-specific bronchial hyperreactivity: this refers to the tendency of asthmatic airways to constrict in response to a host of non-specific (that is, non-immunological) stimuli (including, for example, strong smells, cold air, fog, smoke, exercise, aerosol sprays and dust) that would not cause clinically significant bronchoconstriction in non-asthmatics. Bronchial hyperreac- tivity causes excessive cough and contributes to bronchospasm, which may have different triggers in different patients. Histopathology Asthma is characterized by inflammatory changes throughout the airways, but not the alveoli or lung parenchyma. The inflammation is characterized by the activation of CD4þ helper T lymphocytes, 1 as well as accumulation of leukocytes in the bronchial mucosa (Figures 1 and 2), 2 although these changes do not allow a definitive diagnosis on histopathological grounds. Typically, there is an abundance of eosinophils but some chronic, severe asthmatics show a more prominent neutrophil leukocyte infiltrate. 3 Mast cells are present in the bronchial mucosa but they are not particularly abundant. It has so far not been possible to associate aetiological subdivisions of asthma with reproducible and discernible variability in histopathology, although there is intense interest in this possibility and its possible implications for tailored therapy. 3 Asthma is also associated with structural changes in the airways, collectively termed ‘remodelling’ (Figure 3). 4 These include hypertrophy and hyperplasia of airways smooth muscle cells, increased numbers of mucous goblet cells in the airways epithelium, laying down of fibrous proteins (including collagen, fibronectin and tenascin) beneath the epithelial basement membrane and in the submucosa, and neovascularization (proliferation of vascular capillary beds within the submucosa). Pathophysiology Asthmatic inflammation appears to be coordinated principally by activated CD4þ T lymphocytes of the Th2 type phenotype, Figure 1 Section of an airway from a patient who died of acute asthma stained with haematoxylin and eosin. Eosinophils (‘eosin loving’) cells stain pink because of their basic proteins. Note the intense eosinophil infiltrate in the submucosa A the bronchial epithelium B and surrounding the large mucus plug which is occluding the lumen of the bronchiole C. Chris Corrigan MA MSc PhD FRCP is Professor of Asthma, Allergy and Respiratory Science at King’s College London School of Medicine and the MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, and Consultant Physician at Guy’s and St Thomas’ NHS Foundation Trust, London, UK. Competing interests: Dr Corrigan has received funding to attend meetings and conferences from Schering-Plough, Allergy Therapeutics, Meda AB, UCB Pharma, Novartis, Teva Pharmaceuticals, undertaken research collaborations with GlaxoSmithKline, Novartis, ALK-Abello, Allergy Therapeutics, Leti and acted as a consultant for Meda AB, GlaxoSmithKline, Novartis, Merck Sharpe Dohme and Allergopharma Joachim Ganzer AB. None of these interests is of any relevance to this article. PRINCIPLES OF ASTHMA MEDICINE 40:5 223 Ó 2012 Elsevier Ltd. All rights reserved.

Mechanisms of asthma

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PRINCIPLES OF ASTHMA

Mechanisms of asthmaChris Corrigan

AbstractAsthma is a syndrome of variable airflow obstruction. It is characterized

pathologically by bronchial inflammation and remodelling changes, phys-

iologically by bronchial hyperresponsiveness, and clinically by cough,

chest tightness and wheeze. Cytokines secreted by CD4þ Th2 type

T cells play a major role in coordinating asthmatic bronchial inflammation,

while other effector cells, such as myofibroblasts, epithelial cells, smooth

muscle cells and endothelial cells (activated partly by Th2 type cytokines

and partly by other mediators), play an intermediary role in airways

damage and remodelling. Although the pathological changes in the

airways in association with asthma are now well described, there is

a gap in our understanding of precisely how these changes cause clinical

symptoms. A key aetiological trigger factor for asthma is exposure to

environmental antigens, in particular inhaled allergens, including occupa-

tional allergens and infectious agents, which are probably a major drive to

T cell activation in asthma. Genetic factors governing the production of

T cell cytokines and their actions on target cells, as well as variability in

the structure and development of the mesenchymal elements of the bron-

chial mucosa influence the risk of developing asthma. Many other envi-

ronmental agents exacerbate asthma, but the evidence that they cause

disease is much less clear.

Keywords Asthma; atopy; cytokine; eosinophil; pathogenesis; remod-

elling; T cell

Clinical pathology

The diagnosis of asthma is made on the basis of typical symp-

toms and abnormalities in lung function. The key clinical

features of asthma include:

Variable airways obstruction: airways obstruction in asthma, as

measured by spirometry, may vary spontaneously from none to

severe in the course of hours to minutes, and improves after

suitable therapy. Obstruction, particularly of the smaller airways,

in asthmatics causes shortness of breath, impaired exercise

tolerance, tightness in the chest that may be perceived as

Chris Corrigan MA MSc PhD FRCP is Professor of Asthma, Allergy and

Respiratory Science at King’s College London School of Medicine and the

MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, and

Consultant Physician at Guy’s and St Thomas’ NHS Foundation Trust,

London, UK. Competing interests: Dr Corrigan has received funding to

attend meetings and conferences from Schering-Plough, Allergy

Therapeutics, Meda AB, UCB Pharma, Novartis, Teva Pharmaceuticals,

undertaken research collaborations with GlaxoSmithKline, Novartis,

ALK-Abello, Allergy Therapeutics, Leti and acted as a consultant for Meda

AB, GlaxoSmithKline, Novartis, Merck Sharpe Dohme and Allergopharma

Joachim Ganzer AB. None of these interests is of any relevance to this

article.

MEDICINE 40:5 223

wheeze, and chest hyperinflation (small airways obstruction

prevents complete emptying of the alveoli, causing gas trapping).

Non-specific bronchial hyperreactivity: this refers to the

tendency of asthmatic airways to constrict in response to a host

of non-specific (that is, non-immunological) stimuli (including,

for example, strong smells, cold air, fog, smoke, exercise, aerosol

sprays and dust) that would not cause clinically significant

bronchoconstriction in non-asthmatics. Bronchial hyperreac-

tivity causes excessive cough and contributes to bronchospasm,

which may have different triggers in different patients.

Histopathology

Asthma is characterized by inflammatory changes throughout

the airways, but not the alveoli or lung parenchyma. The

inflammation is characterized by the activation of CD4þ helper

T lymphocytes,1 as well as accumulation of leukocytes in the

bronchial mucosa (Figures 1 and 2),2 although these changes do

not allow a definitive diagnosis on histopathological grounds.

Typically, there is an abundance of eosinophils but some

chronic, severe asthmatics show a more prominent neutrophil

leukocyte infiltrate.3 Mast cells are present in the bronchial

mucosa but they are not particularly abundant. It has so far not

been possible to associate aetiological subdivisions of asthma

with reproducible and discernible variability in histopathology,

although there is intense interest in this possibility and its

possible implications for tailored therapy.3

Asthma is also associated with structural changes in the

airways, collectively termed ‘remodelling’ (Figure 3).4 These

include hypertrophy and hyperplasia of airways smooth muscle

cells, increased numbers of mucous goblet cells in the airways

epithelium, laying down of fibrous proteins (including collagen,

fibronectin and tenascin) beneath the epithelial basement

membrane and in the submucosa, and neovascularization

(proliferation of vascular capillary beds within the submucosa).

Pathophysiology

Asthmatic inflammation appears to be coordinated principally by

activated CD4þ T lymphocytes of the Th2 type phenotype,

Figure 1 Section of an airway from a patient who died of acute asthma

stained with haematoxylin and eosin. Eosinophils (‘eosin loving’) cells

stain pink because of their basic proteins. Note the intense eosinophil

infiltrate in the submucosa A the bronchial epithelium B and surrounding

the large mucus plug which is occluding the lumen of the bronchiole C.

� 2012 Elsevier Ltd. All rights reserved.

Histamine

Mast cell

IL-4 IL-1 3

IL-4 IL-13, TGF-β

Th2 T cell Eosinophil

B cell

Epi

Fib AHR

Remodelling

Narrowing

Acute bronchospasm

ASM

IL-4IL-13 TGF- β

IL-5

Major basic proteins

Leukotrienes

IgE

Allergen

Other antigens?

ACUTE

CHRONIC

Prostaglandin D2

Leukotrienes

DC

B

CD4+

An overview of asthma pathogenesis

Th2-type, CD4+ T cells are activated by allergens and perhaps other antigens following presentation of specific epitopes by dendritic cells (DC). The T cells produce

the cytokines interleukin-4 (IL-4), IL-5 and IL-13. IL-5 promotes eosinophil recruitment to, and survival in, the airways mucosa. IL-4 and IL-13 contribute and also act on epithelial cells (Epi), fibroblasts (Fib) and airways smooth muscle cells (ASM) to cause remodelling changes. Eosinophils damage the mucosa through the release of basic proteins and exacerbate bronchospasm, vascular leakage and oedema through the release of leukotrienes. They also contribute to remodelling through release of pro-fibrotic mediators, such as transforming growth factor (TGF)-β. IL-4 and IL-13 cause IgE switching in B cells, promoting their secretion of allergen-specific IgE. Cross-linking of this IgE by allergens on the surface of mast cells in atopic subjects causes degranulation, with release of mast cell mediators (histamine, prostaglandins and leukotrienes). This is a mechanism for acute exacerbation of symptoms superimposed on the chronic inflammatory background created by T cells and their cytokines. AHR, airways

hyperresponsiveness.

Figure 2

PRINCIPLES OF ASTHMA

characterized particularly by the production of the cytokines

interleukin (IL)-4, IL-13 and IL-5 (see Figure 2).1 These cytokines

are implicated in causing eosinophil accumulation, since IL-4 and

IL-13 up-regulate adhesion molecules in the capillary endothe-

lium of the bronchial mucosa, resulting in increased adhesion

and diapedesis of eosinophils. Once in the tissues, IL-5 prolongs

the survival of eosinophils and primes them for increased release

of their basic granular proteins and production of other media-

tors, in particular cysteinyl leukotrienes, which promote vascular

leakage and thus oedema of the lining of the airways, and are

also the most potent natural bronchoconstrictors so far

described.5 All of these effects probably contribute to airways

obstruction.6

The cytokines IL-4 and IL-136 appear to be vital for remodelling.

They act directly on various structural cells of the airways (such as

epithelial cells) to induce mucous hyperplasia, and indirectly on

others (such as endothelial cells) to induce production of further

remodellingmediators, such as vascular endothelial growth factor

(VEGF), which in turn promotes angiogenesis. Also of emerging

importance is the Th2-type cytokine IL-25 which, in addition to

promoting memory Th2 T cell survival, has a number of direct

effects on remodelling such as angiogenesis.7 Activated eosino-

phils produce a growth factor (transforming growth factor

(TGF)-b) that acts on fibroblasts, causing them to proliferate and

transform into myofibroblasts, an intermediary between fibro-

blasts and smooth muscle cells, which are responsible for the

laying down of fibrous proteins in the bronchial mucosa. TGF-

b and other growth-regulating cytokines also cause increased

MEDICINE 40:5 224

proliferation of airways smooth muscle cells. Injured epithelial

cells also release TGF-b, forming the so-called ‘epithelial mesen-

chymal trophic unit’, which may also contribute to remodelling

changes in asthmatic airways.8 Thus, cytokines derived largely

from T cells are thought to drive most of the inflammatory and

airways structural changes characteristic of asthma, regardless of

its aetiology (Figure 4). Airways structural cells, as well as other

infiltrating leukocytes, including eosinophils and mast cells, are

likely also to contribute to the production of cytokines and growth

factors causing airways remodelling. In addition, there is evidence

that bronchial smooth muscle itself behaves abnormally in

asthma9 and that the stress of repeated bronchoconstriction may

actually cause some of the remodelling changes.10

Finally, IL-4 and IL-13 are the only human cytokines that

induce B lymphocytes to switch to IgE synthesis following acti-

vation by interaction with antigen-specific T cells (see Figure 2).

These cytokines are therefore implicated in the pathogenesis of

atopy (a propensity for inappropriate production of IgE anti-

bodies against antigens or ‘allergens’, encountered at mucosal

surfaces and detected by skin prick or laboratory tests).

Inflammation and asthma therapy

Corticosteroids strongly inhibit T cell pro-inflammatory cytokine

production1; in the bronchial mucosa of asthmatics, they reduce

infiltration of inflammatory granulocytes such as eosinophils. In

contrast, corticosteroids have few direct inhibitory effects on gran-

ulocytes, andmaynot reverse remodelling changes. Other actions of

� 2012 Elsevier Ltd. All rights reserved.

Features of airways remodelling in asthma: laying down of

fibrous protein beneath the epithelial basement membrane

causing apparent thickening (top), hypertrophy and hyperplasia

of airways smooth muscle (middle), and hypertrophy and

hyperplasia of epithelial mucous glands (bottom).

Figure 3

Activated, CD4+ Th2 cells produce many cytokinesimplicated in asthma pathogenesis

All of these cytokines are potential molecular targets in asthma but their redundancy of function, coupled with lack of knowledge as toprecisely how the pathological changes they induce cause clinical symptoms, has hindered therapeutic advances. AHR, airways hyperresponsiveness; IL, interleukin; TNF, tumour necrosis factor.

eosinophil and basophil activation

IL-9, IL-13

IL-4, IL-9, IL-13 mucushypersection

IL-4, IL-5, IL-9, IL-13

IL-4, IL-13 IgE switching

IL-4, IL-9, IL-13 mast cellactivation

TNF-α smooth muscle activation, remodelling

CD4+

Inflammatory Th2

T cell

AHR

Figure 4

PRINCIPLES OF ASTHMA

corticosteroids, such as reduction of vascular leakage, may also be

relevant to reducing mucosal oedema, thereby improving airways

obstruction and bronchial hyperresponsiveness. Whereas cortico-

steroids reduce production of pro-inflammatory cytokines, they

actually increase T cell production of the anti-inflammatory cyto-

kine, IL-10, a key product of a T cell subset called T regulatory cells,

which are now thought to play a role in immune homoeostasis.11

Cysteinyl leukotrienes are important pro-inflammatory prod-

ucts of cells implicated in asthma, particularly eosinophils.5 They

havemany effects thatmay be relevant to asthmapathophysiology,

such as capillary leakage, bronchoconstriction and further eosin-

ophil recruitment. Cysteinyl leukotriene receptor blockers have

a proven role in the treatment of some, but not all asthmatics.

b2-adrenoreceptor agonists relax bronchial smooth muscle and

are useful as ‘reliever’ therapy for acute symptoms of asthma. They

have not been shown convincingly to exert an anti-inflammatory

effect in asthma, although there is some evidence that long-

acting b-agonists may enhance some of the anti-inflammatory

effects of corticosteroids.

A recent therapeutic innovation for asthma is omalizumab,

a humanized monoclonal antibody that binds to the constant

MEDICINE 40:5 225

region of the IgE molecule, holding it in the circulation and

preventing its binding to high-affinity receptors on mast cells and

basophils and low-affinity IgE receptors on B cells and antigen-

presenting cells.12 Omalizumab, administered by intermittent

subcutaneous injection, reduces the frequency of severe exacer-

bations of asthma and sometimes spares corticosteroid therapy.

This confirms a mechanistic role for IgE in asthma, although it is

not clear if omalizumab acts primarily by reducing IgE-induced

mast cell degranulation, IgE-mediated capture of antigens by

B cells and other antigen-presenting cells, or by as yet uniden-

tified mechanisms.

Aetiology of asthma

Genetic susceptibility

The risk of developing asthma tends to run in families. Twin

studies estimate the proportion of asthma risk to be 50e60%

genetically determined, although it is likely that there are

extensive and complex interactions of gene effects with envi-

ronmental influences.13 Genome screens have linked inheritance

of various chromosomal regions with an increased risk of

asthma. Some of these regions contain genes encoding cytokines,

such as IL-4 or IL-13, or their receptors, implicated in asthma

pathogenesis, suggesting that genetic variability in the expression

or actions of these mediators may contribute to asthma risk.

More recent positional cloning strategies have identified new

genes, such as ADAM33, the products of which do not play a role

in known asthma pathways but are involved in the normal

development of the airways during embryogenesis; this raises the

fascinating possibility that variability, as yet uncharacterized, in

� 2012 Elsevier Ltd. All rights reserved.

PRINCIPLES OF ASTHMA

the structure or development of the airways predisposes some

individuals to asthma.14

Role of allergen exposure

When atopic patients inhale allergens to which they are clinically

sensitized through the production of allergen-specific IgE, the

result is cross-linkage of surface-bound IgE on mast cells within

the respiratory mucosa, causing them to degranulate acutely and

release inflammatory mediators, in particular histamine, prosta-

glandin D2 and leukotrienes. These mediators make asthma

acutely worse, since they all cause bronchial smooth muscle

contraction, vascular leakage and inflammatory cell recruitment.

Thus, allergen exposure is an important immunologically specific

trigger in some, but not all, asthmatics, acting on the background

of mucosal inflammation instigated by T cells. These patients

may have other diseases associated with atopy (eczema and

allergic rhinitis).

Early life sensitization to allergens, particularly indoor aller-

gens such as house dust mite, is a major risk factor for the

development of asthma in children, but only in the genetically

predisposed, raising doubts as to whether allergic sensitization is

actually causative of asthma or reflects parallel susceptibility

pathways arising from common genetic origins.15 Many atopic

patients do not develop asthma. Furthermore, asthma developing

later in life is less likely to be associated with atopy, suggesting

that IgE sensitization to allergens is neither necessary nor suffi-

cient for the development of asthma, although further appraisal

of the response, if any, of non-atopic asthmatics to omalizumab

(see above) may reveal that IgE plays a role in asthma even in

patients who are not atopic.

Occupational asthma

Some individuals develop asthma for the first time after exposure

to occupational agents, which may be broadly divided into

reactive chemicals (such as isocyanates) and proteins (such as

wheat flour). Proteins activate T cells directly in the manner of

an inhaled allergen and, like allergens, often induce an associ-

ated IgE response. Reactive chemicals react with native body

proteins such as albumin, creating new antigens that are recog-

nized as ‘foreign’ by T cells. The pathophysiology of occupa-

tional asthma, once developed, appears to be indistinguishable

from that seen in other clinical phenotypes of asthma. Again, it is

not clear what governs individual susceptibility.

Other influences on the development of asthma

Asthma and atopy are, geographically, diseases of developed

countries. This has resulted in speculation about the role of

‘Westernized’ society in their causation.

Pollution and smoking: many pollutants exacerbate asthma but

there is limited evidence that they predispose to its development.15

Air pollution has declined in many Western industrialized coun-

tries while asthma prevalence has increased. Epidemiological and

experimental evidence suggests that diesel exhaust particulates

and ozone promote sensitization to allergens. Exposure of chil-

dren to tobacco smoke in utero or early childhood increases their

risk of developing wheeze. Smoking in adults increases the risk of

developing asthma, including occupational asthma.16 The patho-

physiological mechanisms are unknown.

MEDICINE 40:5 226

Diet: the growth of the fast food diet and escalating obesity have

led to speculation about lack of nutrients (antioxidant vitamins,

omega-3 fatty acids, selenium, magnesium, sodium and zinc)

and obesity playing a role in asthma causation, but there is no

conclusive evidence.17 Obesity itself may be associated with

accelerated decline in lung function so the epidemiological

problems are complex.18 Breast feeding reduces the risk of

eczema in atopic ‘at risk’ children, but the evidence relating to

asthma is inconclusive.

Infection: the pattern of microbial exposure in infancy and

childhood has changed as a result of a cleaner environment and

widespread use of antibiotics and vaccination. The ‘hygiene

hypothesis’ invokes this as a risk factor for asthma and atopy.19

The precise mechanisms are unknown but the hypothesis has

focused research on the effects of alteration of the intestinal flora

early in life, exposure to airborne bacterial products (such as

endotoxins on farms) and the influence of specific (viral,

helminthic) infections on the risk of developing asthma.

Research is ongoing. A

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