Pathophysiology and Airway Remodeling in Asthma

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Pathophysiology and Airway Remodeling in Asthma
NTPAA course Advanced Topics in Immunology
(IMMU 7100) Research Topics in Physiology (PHGY
7190) Andrew J Halayko, PhD Office RS321
Respiratory Hospital (810 Sherbrook),
787-2062 Lab 547 John Buhler Research Centre,
789-3778 (November 2008)
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• Asthma Definition
• Asthma is a disorder of the airways
  characterized by paroxysmal or persistent
  symptoms (dyspnea, chest tightness, wheeze and
  cough), with variable airflow limitation and
  airway hyperresponsiveness to a variety of
  stimuli
• The definition includes these concepts
• Asthma is a chronic inflammatory disease (thus
  without appropriate treatment is progressive)
• There is airflow limitation that is reversible
  (though there is also an irreversible component)
• A variety of stimuli can trigger airways
  response.
• (National Asthma Task Force Prevention and
  management of asthma in Canada, 2000)

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Airway Remodeling the Progression of Asthma
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Airway Hyperresponsiveness Asthma as a
Progressive Disease

• Long-standing asthma
• ? Recently diagnosed asthma

Boulet et al. Am J Respir Crit Care Med 162
1308-13, 2000
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Branching of airways in the human
tracheo-bronchial tree Conducting Airways
ciliated epithelia, mucous, smooth
muscle Respiratory Zones (air velocity 0)
phagocytic cells (alveolar macrophages),
lymphatic channels drain into hilar lymph nodes
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Anatomy of the Airways
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The Anatomy of Airflow Limitation and Airway
Hyperresponsiveness
Baseline Antigen Atropine
Tatalum bronchogram, allergen-sensitized canine,
right lower lobe
Kessler et al, 1975, JAP 3896
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Airway Hyperresponsiveness Provocative Challenge
Test Common Stimuli chemical (eg. histamine,
Mch, ?-agonists, LT, adenosine) physical (eg.
exercise, cold air) sensitizers (eg. allergen)
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Airway Hyperresponsiveness Provocative Challenge
Test Common Stimuli chemical (eg. histamine,
Mch, ?-agonists, LT, adenosine) physical (eg.
exercise, cold air) sensitizers (eg. allergen
PC20 (mg/mL)
Cockroft, 1985 1997
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Measurement of Airway Function Response to
Bronchodilators Common Stimuli chemical (eg.
histamine, Mch, ?-agonists, LT, adenosine)
physical (eg. exercise, cold air) sensitizers
(eg. allergen
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The Deep Breath Phenomenon Structure and
Function in the Lung During Mch challenge, if
NORMAL subjects dont take a deep inspiration,
they respond to Mch the same way as asthmatics!
intrinsic impairment of the ability of
inspiration to stretch airway smooth muscle is a
major feature of asthma(Skloot, Permutt, and
Togias JCI, 962393, 1995)
Why isnt deep breath broncho-protective in
asthma?
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Lung Structure / Function Relationships
Why isnt deep breath broncho-protective in
asthma?

• Normally, there is interdependence of airway
  size and and lung volume a primary determinant
  of airway calibre is lung volume (Mechanical
  coupling of the airways and lung parenchyma, thus
  the size and shape of one affects the other).

Airways are hyperresponsive AND there are altered
structure / function relationships of the airways
in asthma ... the biological mechanism?
Inflammation and remodelling!
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Airways Remodelling Important Concepts

• Changes in airway wall thickness and
  organization, especially evident in severe and
  fatal asthmatics.
• Remodelling in mild asthmatics in children
• Duration of disease determines effectiveness of
  therapy - remodelling in asthma is progressive.
• No clear evidence for reversal of structural
  changes with asthma therapies.
• The cause-effect relationship between the
  components of airways remodelling and altered
  lung function still not fully understood.

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Asthma Pathology Airway Inflammation and
Remodeling
Non-asthmatic
Airway remodeling affects Epithelium submucosa
(fibrosis myofibroblasts) smooth muscle
adventitia (fibrosis) bronchial vasculature
mucus gland goblet cell dysplasia)
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Features of Airway Remodeling Goblet cell and
mucus gland hyperplasia
Asthmatic
Normal subject
Ordonez et al AJRCCM 163, 517-23, 2002
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Airways Remodelling in Asthma Fibrosis

• Thickening of the basement membrane and increase
  matrix deposition throughout the airway wall
• Coll I III
• fibronectin
• laminin 2
• tenascin
• elastin
• versicam
• hyaluronan

Laminin Tenascin
Jeffery AJRCCM., 164S28-38, 2001 Laitinen et al.
Asthma, pp. 209-23, 1997
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Airways Remodeling Submucosal (myo)fibroblasts
Laitinen et al. Asthma, pp. 209-23, 1997
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• Myofibroblast Accumulation Occurs
• 24hrs After Allergen Challenge

Atopic asthmatic diluent
Atopic asthmatic allergen
Atopic non-asthmatic (no challenge)
Non-atopic, non-asthmatic (no challenge)
24 hrs !!
Cell per 0.1 mm2
Myofibro
MC
Eos
Gizycki et al. Am J Respir Cell Mol Biol. 1997
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Subepithelial Myofibroblasts from Asthmatics
Express a Pro-fibrotic Phenotype

IL-4 effects on collagen, MMP-2 TIMP-2
expression
BNF bronchial fibroblast (non-asthmatic
subjects) BAF bronchial fibroblasts
(mild/moderate asthmatic subjects)
MMP-2
TIMP-2
Baseline
IL-4 (6hr)
Pro-collagen I (?1) mRNA
BAF
BNF
BAF
BNF
BAF
BNF
Bergeron et al, Clin Exp Allergy  33 1389-1397,
2003
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Increased ECM Production by Asthmatic ASM
Potentiates Proliferative Responses
Production of ECM proteins
Proliferation of ASM Cells
ECM from Non-asthmatic
Non-asthmatic
ECM from Asthmatic
Asthmatic
ASM Proliferation
Johnson et al, J Allergy Clin Immunol 113
690-696, 2004
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Airways Remodelling Airway Smooth Muscle

• Inflammation fibrosis
• ASM Thickening
• - cellular hyperplasia and hypertrophy
• -Type I and Type II asthma
• Hyperresponsiveness
• - due to altered sensitivity to spasmogens
  dilators, and from increased ASM

Non-asthmatic (SEM of mucosa)
Fatal asthma (SEM of mucosa)
Jeffery AJRCCM., 164S28-38, 2001
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Increased ASM Mass In Mild-to-Moderate and Severe
Asthma

• Mild-to-Moderate Asthma
• Myocyte hyperplasia (gt2x vs. control)
• (Woodruff et al., Am J Resp Crit Care Med
  1691001-1006, 2004)
• Myocyte hypertrophy (lt2x vs. control)
• (Benayoun et al., Am J Resp Crit Care Med
  1671360-1368, 2004)
• Severe Asthma
• Type I (myocyte hyperplasia in proximal airways)
• Type II (proximal myocyte hyperplasia
  hypertrophy along distal airways)
• (Ebina et al., Am Rev Resp Dis 148720-726, 1993)
• Myocyte hypertrophy (gt3x vs. control)
• (Benayoun et al., Am J Resp Crit Care Med
  1671360-1368, 2004)

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Can Airway Remodelling and Associated
Hyperresponsiveness be Reversed?
HDM
naive
5x/wk x 7 wks
BALB/c
HDM extract (25?g intranasal)
A,B - mucin production in epithelial goblet cells
(Alcian blue (pH 2.5)) C,D - subepithelial
collagen (Picro Sirius red) E,F sm-?-actin
Johnson et al 2004 Am J Respir Crit Care
169378-385
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Can Airway Remodelling and Associated
Hyperresponsiveness be Reversed?
5x/wk x 7 wks
9 wks resolution
BALB/c
HDM extract (25?g intranasal)
Area Collagen
Area sm-?-actin
BALF Eos (x106/ml)
Naive
Naive
Naive
3wk HDM
5wk HDM
Resolution
Resolution
3wk HDM
5wk HDM
Resolution
3wk HDM
5wk HDM
Johnson et al 2004 Am J Respir Crit Care
169378-385
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Can Airway Remodelling and Associated
Hyperresponsiveness be Reversed?
5x/wk x 7 wks
9 wks resolution
BALB/c
HDM extract (25?g intranasal)
? naive mice ? 5 wk HDM ? resolution
Airway response to methacholine
Johnson et al 2004 Am J Respir Crit Care
169378-385
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Airways Remodelling Neovascularization
Jeffery AJRCCM., 164S28-38, 2001
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Airways Remodelling Neovascularization
Control
COPD
High-magnification bronchovideoscope

• measures vessel length density vessel area
  density

Asthma Newly diagnosed, steroid-naive
Asthma 5 Yrs, ICS
Tanaka et al. 2004 Am J Resp Crit Care Med
1681495-1499
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Airways Remodelling Mast Cells
Asthmatic subject, airway biopsy

• atopic
• ?nonatopic

Brightling et al. N Engl J Med 346 1699-1705, 2002
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Airway Mast Cells in Persistent Asthma Kraft et
al., Chest, 12442-50, 2003
The Asthma Clinical Research Network

• N45 with clinically stable, persistent asthma
• 35 completed treatment phase 10 randomized
  among groups had treatment failure
• RX failure criteria (exacerbations)
• - need gt1 prednisone
• - gt 1 ER visit
• - hospitalization for asthma
• BAL tryptase shows the same trend as does MC

Median MC /mm2)
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• Asthma Pathophysiology Take Home Messages
• Lung is the end organ bronchi, bronchioles,
  alveloi
• Multi-factorial - allergy genes environment
  phenotype
• Asthma is a progressive disease (if untreated
  perhaps also if treated?)
• Pulmonary function - variable airflow
  obstruction (PEF) airway hyperresponsiveness
  (FEV1)
• Airway inflammation / airway remodelling -
  fibrosis edema inflammatory cells
  hypertrophy/hyperplasia
• epithelium (myo)fibroblasts airway smooth
  muscle mucous glands nerves vasculature
  eosiniphils, neutrophils, lymphocytes (TH1/TH2)
  mast cells