Post on 29-Jul-2018
Remodelling: an important component of asthma
Stephen T Holgate,IIR Division,
School of Medicine,University of Southampton.
sth@soton.ac.uk
Bronchial Mucosal Biopsy from a 7 year old Child with Severe Asthma Despite High Dose
Corticosteroid Treatment
Masson Trichrome stain
Desquamation
BM
EosinophilsEosinophils
Remodelling in asthma:Structural changes of the airway wall
A. Normal Lung B. Asthmatic Lung
Histopathologic Changes that EmbraceAirway Wall Remodelling in Asthma
1. Smooth muscle hypertrophy/hyperplasia2. Subepithelial collagen and glycoprotein deposition3 Extracellular matrix deposition in submucosa, muscle and adventitia4. Mucus gland hyperplasia6. Shedding and metaplasia of epithelium7. Angiogenesis8. Nerve proliferation
Scatter plot showing changes in ASM cell sizein bronchial biopsies
p < 0.001
AS
M c
ell s
ize
(µm
)
Controls
Benayoun L et al. AJRCCM 2003;167:1360-8
p < 0.001
p < 0.001
p < 0.001
p < 0.001
p = 0.003
p = 0.013 p = 0.020
Intermittent asthmatics
Mild to moderate asthmatics
Severe asthmatics
COPD
15 -
10 -
5 -
Relationship between reticular basement membrane thickness and airway smooth muscle
and inner wall area in asthma deaths
Smooth Muscle Inner Wall Area
22 -
20 -
18 -
16 -
14 -
12 -
10 -
8 -
6 -
4 -
2 -
0 2 4 6 8 10
% airway smooth muscle
% inner wall area
Reticular basement membrane thickness, µµµµm
22 -
20 -
18 -
16 -
14 -
12 -
10 -
8 -
6 -
4 -
2 -
0 2 4 6 8 10
Reticular basement membrane
thickness, µµµµm
James AL et al AJRCCM 2002; 166: 1590-5
Eosinophils
Mast cells
Eosinophil
Fibroblast
Endothelium
Epithelium
TGF-ααααFGF-7
FGF-2VEGF
TGF-ββββFGF-2
IL-6, IL-11, TGF−−−−ββββ, NGF
PDGF
ActivationECM synthesis
Mucus hypersecretion
Myofibroblast
TransdifferentiationMigration,
ECM synthesis
DifferentiationMigration
TGF−−−−ββββ,IL-13, IL-4
TNF−−−−ααααAngiogenin
AngiogenesisActivation (intergrin upregulation)
IL-4, IL-13,IL-17
ASM cells
ProliferationProtein synthesis (ECM, GFs, chemokines)
Chronic inflammation and recurrent exacerbations are associated with tissue remodelling
Activation of the epithelial mesenchymal trophic unit in chronic asthma
Th2 inflammationGENES
ENVIRONMENT
allergy
Moderate asthma
Mild allergic asthma
SevereasthmaPollution,
VirusesETS
AIRWAY
Epithelial-mesenchymaltrophic unit
allergen
viruses
Computerised tomography to “visualise”airway wall remodelling in asthma
• High-resolution computed tomography findings are correlated with disease severity in asthma. Harmanci E et al Respiration 2002; 69: 420-6
• Thoracic CT in pediatric patients with difficult-to-treat asthma. Marchac V et al Am J Roentgenol 2002; 179: 1245-52
• Nakano Y et al Quantitative assessment of airway remodelingusing high resolution CT. Chest 2002; 122: 271S-5S
• Clinical assessment of airway remodeling in asthma : utility of computed tomography. Niima A et al Clin Rev Allergy Immunol 2004; 27: 45-58
Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma
Niima A et al Am J Respir Crit Care Med 2003; 168: 983-8
• It has been assumed that airway wall thickness contributed to BHR in chronic asthma
• Helical computed tomography used to assess airway wall thickness in 55 asthmatic patients
• Airway reactivity to methacholinecorrelated negatively with airway wall thickness (r=-0.56)
Increased smooth muscle
Increased matrix deposition
Hyper-echoic band
Hypo-echoic band
Use of endobronchial ultrasound to assess airway
wall thickness in asthmaT
D
L
Airway Wall
T/D ratio = wall thickness/ total airway diameter
T/D ratio using endobronchial ultrasound
Controls Asthmaticsn = 8 n = 10
T/D
(short axis)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
Hyperechoic bands (white) occur at changes of density between air, soft tissue and cartilage.
P<0.004
Direct measurements of the airway wallby endobronchial radial ultrasound identifies
thickening of the large airways in asthma,consistent with structural remodelling
Shaw TJ. et al. Eur Respir J 2004; 23: 813-7
Wall thickness/diameter ratio (T/D)vs Hyperresponsiveness
PC20 Histamine (mg/ml)
0.1 1 10
T/D
0.12
0.14
0.16
0.18
0.20
0.22
0.24
0.26
0.28
0.30
r = 0.708p < 0.01
Percentage wall area (%WA)vs Hyperresponsiveness
PC20 Histamine (mg/ml)
0.1 1 10
%W
A
54
56
58
60
62
64
66
68
70
72
r = 0.560p < 0.05
Relationship between airway wall thickness and airway hyperresponsiveness
? Remodelling starts as a protective response to repeated bronchoconstriction by creating a stiffer airway
Per
cent
age
Wal
l Are
a
Wal
l thi
ckne
ss/d
iam
eter
rat
io
EBUS to assess airway wall thickness in reversible and “fixed” asthma compared to normal controls
Normal Reversible “Fixed”
Inne
r w
all a
rea
(mm
2
P=0.002P=0.03
Helium ion microscopy and atomic force microscopy of asthmatic airway collagen fibrils
HeIM image of collagen (top) and AFM height image of an asthmatic biopsy section showing interstitial collagen type I fibrils in inner airway wall (right). The line section in the inset shows the typical D-banding of
Immuno-reactive soluble matrix components in BALfrom normal & asthmatic subjects
0
0.05
0.1
0.15
0.2
0.25
0.3
Co
llag
enV
I (n
g/m
l)
p = 0.004
p = 0.008
p = 0.003
normal atopy mild/mod asthma
severe
0
1
2
3
4
5
6
7
normal atopy Mildasthma
severe
Lam
inin
(ng
/ml)
p = 0.120
p = 0.123
p = 0.113
Collagen VILaminin
0
1
2
3
4
5
6
7
Ten
asci
n(n
g/m
l)
p = 0.013
p = 0.016
p = 0.056
normal atopy mild/mod asthma
severe
Tenascin C
Healthy Controlsn=10
Mild Asthman=9
Severe Asthman=10
Inte
rstit
ial
imm
unor
eact
ivity
(% a
rea
of b
iops
y)
10
20
30
40
50
60
70
p=0.004
p=0.05
p<0.0001
Collagen III
Inte
rstia
lIm
mun
orea
ctiv
ity(%
area
of b
iops
ies)
Healthy controls Mild asthma Severe asthman=10 n=9 n=10
Immuno-reactive matrix components in bronchial biopsies from normal & asthmatic subjects
Risk factors for airway remodelling in asthma manifested by post-bronchodilator FEV1/FVC ratio: a longitudinal population
study from childhood to adulthood.Rasmussen F et al. Am J Respir Crit Care Med 2002; 165:1480-8
• At age 18 & 26 yrs: low FEV1/FVC ratio in 7.4 & 6.4%.
• From age 9-26 yrs those with consistently low ratios showed 2x greater decline in lung function over time.
• Asthma, BHR, low lung function in childhood & male sex independently associated with low ratio & accelerated decline in lung function.
• Airway remodelling begins in childhood continues into adult life.
Do corticosteroids prevent or reverse remodelling in asthma ?
• Corticosteroids have been shown to reduce the thickness of the reticular basement membrane & number of microvessels but have no effect on smooth muscle mass.
(Chetta A et al. Am J Respir Crit Care Med. 2003; 167: 751-7).
• Long term intervention studies of inhaled corticosteroids in childhood asthma (CAMP & START) showed little or no effects on post bronchodilator FEV1.
• “The effects of corticosteroids on remodelling seems to vary a great deal: some aspects are responsive while others are not or less so ….It is likely that when used optimally corticosteroids will have limited efficacy overall”. (Ward C , Walters H. Curr Opin Clin Immunol 2005; 5: 43-8).
Contrast between normal and asthmatic airways
NormalNormal Severe AsthmaSevere Asthma
Allergy InflammationStructural
changes
SYMPTOMS
While inhaled steroids suppress inflammation they do not influence the underlying natural history of asthma (the
PEAK study; Prevention of Early Asthma in Kids)
Fluticosone, 88µµµµg bd
Placebo
Guilbert TW et al N Eng J Med 2006; 354: 1985-7
N=285, aged2-3 yrs
Remodelling results from injury to airway from repeated cycles of inflammation and repair
Environmental trigger
Intact epithelium Impaired repairDamaged epithelium
Growth factors and cytokines
Chronic inflammation
Fibroblastproliferation
Myofibroblastactivation
TGF-ββββEGF
Remodelling
Asthma Eotaxin
Mast cell
ET-1 andVEGF
Adapted from Boxhall C, et al. Eur Respir J 2006
Growthfactors
Growthfactors
Is chronic asthma the consequence of altered epithelial repair leading to a chronic wound scenario, chronic
inflammation and remodelling?
Impaired Epithelial Repair Augments TGFβ2 Release
Scrape wounded+ EGF + AG1478
Scrape wounded+ EGF
Unwounded + EGF+AG1478
SFM
EGF
EGF + AG1478
Puddicombe et al FASEB J 2000
Epithelial cell repair in vitro is impaired in paediatric asthma Kicic A. et al. Am J Respir Crit Care Med. 2010; 181: 889-98.
Airway plugging in fatal asthmaHypersecretion of mucus: A response to epithelialinjury and a major therapeutic target in asthma
Growthfactors
Fibroblasts
Smooth muscle
Microbial
components
Epithelium
Air
Pollutants
Allergens and
Chemicals
Growthfactors
Dendriticcells
Th-2 cells
Eosinophils
mast cells
SPDEF↑ STAT6↑FoxA2↓
Goblet cell metaplasia
IL-4/13
Bronchial epithelium can be programmed to orchestrate both Th2 inflammation and remodelling
X X XX
Th2IL33, TARC, IL13, eotaxin
Epithelial Damage- Barrier loss- Macromolecular permeability
Damaging Agents
Proliferation and Differentiation- Ciliagenesis- Secretory function
Interim Repair- Barrier restored- Secretory cell function
Immediate Response- Formation of temporary barrier
Leaky
TGFβ
MMPs, collagen,Junctional proteins
Fibroblast proliferation, Myofibroblast activation
Resolution: healing by primary intention
Incomplete repair:
healing by secondary intention
Chronic inflammationRemodelling
Leaky
EMTUInjury, repair, remodelling
inflammation
Immunological Development
PERSISTENT ASTHMA
Virus-related wheeze
Atopy
Viruses, Tobacco smoke, Allergens,Air pollution
allergens, exercise,
cold airirritants
External Environment, tobacco smoke, viruses, allergen
(Th1, Th2)
epitheliumVulnerable
airway structure Innate immunity
BHR
Birth
Adulthood
Age 3-5
Puberty
inflammation
BHR
ASTHMA
Mechanical strain
epithelium
Lung Morphogenesis
Immunological DevelopmentPrenatal
External Environment
In utero
EMTUInjury, repair, remodelling
inflammation
Immunological Development
PERSISTENT ASTHMA
Virus-related wheeze
Atopy
Viruses, Tobacco smoke, Allergens,Air pollution
allergens, exercise,
cold airirritants
External Environment, tobacco smoke, viruses, allergen
(Th1, Th2)
epitheliumVulnerable
airway structure Innate immunity
BHR
Birth
Adulthood
Age 3-5
Puberty
inflammation
BHR
ASTHMA
Mechanical strain
epithelium
Lung Morphogenesis
Immunological DevelopmentPrenatal
External Environment
In utero