Airway remodeling in asthma

Airway remodeling in asthma
17/5/2013 Suparat Sirivimonpan, MD

Outline
• Introduction
• Histopathological features of remodeling
• Mechanism of airway remodeling
• Clinical relevance of remodeling
• Effect of asthma therapy on airway remodeling

Introduction
Asthma
• common chronic disorder of the airway
• is characterized by the complex interaction of
– airway obstruction
– bronchial hyperresponsiveness (BHR)
– airway inflammation
 leads to recurrent episodes of wheezing, breathlessness,
chest tightness, and coughing
Manuyakorn W,et al. APJAI 2013;31:3-10

Introduction
• The airway inflammation is typically eosinophillic ,
elevation of Th2 cytokines
• However, TH2 inflammation alone cannot explain all
features of asthma
• Furthermore, whilst recognized to modify eosinophilic
inflammation, inhaled corticosteroid treatment in atopic
children with recurrent wheezing has been shown to
have no effect on decline in lung function and the natural
history of asthma over time

N Engl J Med 2006;354:1985-97.

Introduction
• Airway remodeling is strongly suspected to result in the
physiologic subphenotypes of irreversible or partially
reversible airflow obstruction and accelerated lung
function decline
Curr Opin Allergy Clin Immunol 2013, 13:203–210
J Allergy. 2012;2012:316049
Inflammation
and
Remodeling !!

Histopathological features of
remodeling

Airway remodeling
• Airway remodeling : structural alterations
• wide array of pathophysiologic features
Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
1. Epithelial changes
2. Increased smooth muscle mass
3. Increased numbers of activated
fibroblasts/myofibroblasts
4. Subepithelial fibrosis
5. Vascular changes (angiogenesis)

Epithelial alterations
• Morphologic changes to airway
epithelium : key feature
• Epithelial alterations :
– shedding of the epithelium
– loss of ciliated cells
– goblet cell hyperplasia
– upregulation of growth
factors, cytokines, and
chemokines
Epithelial
shedding

Epithelial alterations
• Barrier function of the airway epithelium in asthmatic
patients is dysfunctional
– breakdown in epithelial tight junction integrity
– impaired repair after injury
• However, epithelial changes are not necessarily specific
to asthma
– can be observed in patients with various pathologic conditions of
the lung
J Allergy Clin Immunol 2007;120: -

Mucus secretion and goblet cells
• Mucus hypersecretion of the mucins MUC5AC and
MUC5B by goblet cells
• Upregulation of mucin synthesis and development of
goblet cell hyperplasia
- TH2 cytokines (predominantly IL-9 and IL-13)
- IL-1β, TNF-
- COX-2 and their associated intracellular signaling
pathways

Subepithelial layer thickening
• increased deposition of extracellular matrix proteins
(ECMs)
• Subepithelial basement membrane thickening is
confined to the lamina reticularis (reticular basement
membrane - RBM)
The true basement membrane(lamina rara and lamina
densa) is not altered in thickness in asthma

• consists of a dense layer of fibrillar collagens
• composed of collagen I, III and V and fibronectin
• Laminin and collagen IV is unaltered in asthma

• Major cells (ECMs production) are fibroblasts,myofibroblasts
• In an inflammatory environment
epithelial cells release growth factors (TGF-β)
fibroblasts are activated/differentiated into myofibroblasts
secrete proinflammatory mediators and ECM proteins
“Epithelial mesenchymal
trophic unit (EMTU)”
as an integrated component within the
airways of relevance to asthma

Airway smooth muscle hyperplasia
and hypertrophy
• Smooth muscle layer in the airways is increased by
– 50-200% in fatal asthma
– 25-55% in non-fatal asthma
compared with normal subjects
• These changes could be from smooth muscle cell
hyperplasia, hypertrophy or increased ECMs between
cells
Clin Exp Allergy. 2005;35:703-7

Airway smooth muscle hyperplasia
and hypertrophy
• ASM cells are biologically active and may participate in
the remodeling process through the synthesis of ECMs
in response to growth factors (TGF-β, VEGF, and CTGF)
and serum from asthmatic patients
• Increased airway smooth muscle mass has been
suggested to be responsible for the pathophysiology of
airway hyperresponsiveness

Angiogenesis
• abnormal increase in the number and size of
microvessels within bronchial tissue in remodeled airways
• mainly below the basal lamina in the space between the
muscle layer and the surrounding parenchyma
• An imbalance between vascular endothelial growth factor
(VEGF) and angiopoietin-1 has been shown to be
involved in these abnormalities

Angiogenesis
• VEGF : increasing the permeability of these abnormal
blood vessels
– vessel dilation and edema  airway narrowing
– source of inflammatory cells and plasma-derived
mediators and cytokines

• role for tissue factor (TF), a primary initiator of blood coagulation,
secreted by bronchial epithelium after mechanical stress on
angiogenesis of asthmatic airway
J Allergy Clin Immunol. 2012;130:1375-83

Mechanisms of Airway
Remedeling

Mechanisms of airway remodeling
• Inflammation and Inflammatory mediators
• Epithelial injury
• Physical forces
• Cell-cell interactions
• Imbalance between repair and removal of ECM
proteins

Inflammation
• driving force behind most features of airway remodeling
• Multiple cytokines, chemokines, and growth factors
released from both inflammatory and structural cells in
the airway tissue create a complex signaling
environment that drives airway remodeling

Inflammation
• IgE and mast cells : acute response
• Eosinophils , T-cell esp TH2 cells : late response
– Eosinophils : highly basic granule-associated proteins
– TH2 cells : cytokines, such as IL-4, IL-5, IL-9, and IL-13
• Eosinophils play a critical role in tissue remodeling
– main source of the profibrotic cytokine TGF-β  tissue
remodeling
– support fibroblast proliferation, collagen synthesis, and
myofibroblast maturation

Inflammation

Stephen T. Holgate, .Middleton’s Allergy 7’th edition ,893-915.
important role for airway epithelial cells in initiating and maintaining the remodeling
process through their interactions with subepithelial mesenchymal cells

Epithelial-Mesenchymal Trophic Dysfunction
• associated with broad functional activation of the airway
epithelium, with expression of many molecules that are
relevant to the remodeling process
– transcription factors nuclear factor kappa B (NF-κB)
– STAT-1, and STAT-6
– enzymes COX-2
– inducible nitric oxide synthase (iNOS);
– peptide endothelin
– proinflammatory cytokines such as IL-1β and GM-CSF
– growth factors such as PDGF, bFGF, and TGF-β

Epithelial loss
Reticular basement membrane thickness
Am J Respir Crit Care Med. 2008;178:476-82

Number of vessels
Eosinophils

IL-4+ cells
IL-5+ cells
All pathologic features examined were
similar in nonatopic and atopic children

J Allergy Clin Immunol 2012;129:974-82
Severe therapy resistant
asthma

Airway remodeling

STRA Control
Eosinophilia

Remodeling can occur independently of
Th2 inflammation
TH2 cytokine

Epithelial injury
• Both inflammatory and functionally active structural
components are equally involved
• Asthma primarily develops because of serious defects in
the epithelial layer
 environmental allergens, microorganisms, and toxins
greater access to the airway tissue
 impaired repair process that drives the inflammatory
and remodeling responses in the underlying submucosa

Epithelial injury
Environmental (pathogens, allergens, pollutants, and cigarette smoke)
or mechanical stress factors resulting in epithelial injury
release of mediators from the epithelium
ex. TGF-β and chemokines
subepithelial fibrosis and increased ASM mass
“Epithelial-mesenchymal interactions”

Physical forces
• may potentially arise in several ways, such as
– during inspiration-expiration
– Cough
– Bronchoconstriction from airway smooth muscle
contraction during asthma exacerbation
• Airway smooth muscle contraction produces a
compressive stress on the airway epithelium, fibroblasts
and smooth muscle itself
 airway structural changes or airway remodeling

Physical forces
• Role of physical forces on airway structural cells
responses involved in airway remodeling
– increased cell proliferation
– increased deposition of ECMS
– subepithelial layer thickness
– promoted smooth muscle cells migration
– production of contractile enzyme and VEGF

Mild atopic asthma
4 group
• dust-mite allergen (Dermatophagoides pteronyssinus)
• methacholine
• albuterol followed by methacholine
• saline
N Engl J Med 2011;364:2006-15

N Engl J Med 2011;364:2006-15
Airway eosinophil recruitment
Epithelial repair & structural remodeling

Before;
Collagen type III
After;
Collagen type III
Before;
Goblet cells
After;
Goblet cells
Methacholine Challenge
Bronchoconstriction induces epithelial
stress and initiates a tissue response that
leads to structural airway changes

Cell-cell interactions
• critical for the interaction of many inflammatory and
structural cells leading to airway tissue remodeling
• CD4+ T cells might directly enhance ASM proliferation
through cell cell interactions increased AHR
• activated T lymphocytes, eosinophils, neutrophils, and mast
cells interact with ASM cells through ICAM-1 ,VCAM-1 
upregulation of cell adhesion molecules and the stimulation of
DNA synthesis in ASM cells

Imbalance between repair and removal
of ECM proteins
• ECM proteins form a network of collagenous and
noncollagenous structures that surrounds cells in the
airway tissue
• The main ECM elements include
– collagens, elastic fibers, fibronectin
– MMP (metalloprotease): MMP-1, MMP-2, MMP-9, MMP-12
– TIMP-1 and TIMP-2, which are inhibitors of MMPs

• The interaction between
– inflammatory cells
– structural cells (e.g. epithelial cells and fibroblasts)
– turnover rate of extracellular matrix proteins (ECMs)
determines the net balance of remodeling and fibrosis
within the airways
• ASM cells secrete MMPs,TIMPs

Imbalance between repair and removal
of ECM proteins
• Abnormal deposition of ECM elements in
– submucosal and adventitial areas of the large and small airways
– ASM layer
• ECM composition within the ASM layer might constrain
shortening of the ASM bundles and prevent excessive
airway narrowing
 fibrosis of the airway wall might protect against the
collapse of the airway lumen by an exaggerated
contraction of the increased ASM mass

Clinical relevance of
remodeling

Structural-physiologic relationship
• Remodeling is assumed to result in
– persistent airflow limitation
– decrease in lung function
– AHR
• Structural changes in the asthmatic airway , particularly
increased smooth muscle mass, angiogenesis, and
subepithelial fibrosis  airflow limitation
• cellular infiltration in the asthmatic airways  decrease
in lung function

The airway wall thickness as assessed by HRCT in the asthmatic airway was
demonstrated to inversely correlate with airway hyperresponsiveness
It was proposed that the thickening with deposition of
the matrix proteins may exert a protective mechanism
by increasing the stiffness of the airways to attenuate
the sporadic bronchoconstriction

Current asthma medication
and Airway remodeling

Asthma medication
• Inhaled corticosteroids (ICS)
• ICS plus LABA
• Leukotriene receptor antagonists
• Omalizumab

ICS
N Engl J Med 2006;354:1985-97.

ICS
Durrani SR,et al. J Allergy Clin Immunol 2011;128:439-48

Corticosteroids
• Role of corticosteroids in reversing airway remodeling
remains controversial
• Corticosteroid dose and duration of administration are
important considerations when evaluating the effects of
treatment on remodeling
• The doses needed to affect a change are thus beyond
the dose clinically used by many patients
• The use of such high doses : potential for adverse
effects esp. growth in children

ICS plus LABA
• 30 moderate asthmatic patients (adults) VS 30 control
subjects
• Symbicort 4.5/160 μg twice daily for one year
• Result :
– decreases in MMP-9, TIMP-1, and TGF-β levels in
sputum samples
– decreased airway wall thickness, as assessed by
means of HRCT with ICS/LABA treatment
Acta Pharmacol Sin. 2011;32:126-32

ICS plus LABA
• There is an absence of studies comparing combination
therapy versus ICSs alone on human airway remodeling
• β-adrenergic agents could affect aspects of remodeling
 anti-bronchoconstrictor influence protecting against
airway mechanotransductive effects

LTRA
• Murine model
• Montelukast
– reduction in airway eosinophilic infiltration and goblet cell
metaplasia
– reversal in the established increase in ASM mass and
subepithelial collagen deposition
Saline MontelukastOVA
Am J Respir Crit Care Med. 2006;173:718-28.

Omalizumab
• Severe persistant allergic asthma
– reduce airway wall thickness in severe asthmatic subjects as
evaluated by HRCT
Changes in airway measurements after 16 weeks of treatment with and without omalizumab versus baseline
Data are expressed as medians. p < 0.01
Respiration. 2012;83:520-8

Novel treatment
• Anti IL-5 : Mepolizumab
• Anti IL-13 : Lebrikizumab
• Anti-TNFα : Etanercept, Golimumab ?

Conclusion
• inflammation and remodeling can occur as separate but
parallel aspects of the asthmatic process
• Airway remodeling represents complex multicellular
processes

Conclusion
• Remodeling is assumed to result in
– persistent airflow limitation
– decrease in lung function
– AHR
• Inhaled corticosteroids
– limited influence on remodeling
– dose and duration of treatment

Conclusion
• Despite advancements in the recognition of key cellular
and molecular mechanisms involved in remodeling
it is unclear as to
– when is the best time to initiate treatments to modify
remodeling?
– which components to target?
– how best to monitor interventions on remodeling?
need to develop new therapeutic approaches or
interventions to specifically target components of airway
remodeling to either prevent or reverse these processes

Airway remodeling in asthma

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