Airway remodeling in asthma

Airway remodeling in asthma17/5/2013 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

Manuyakorn W,et al. APJAI 2013;31:3-10

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 changes2. Increased smooth muscle mass3. Increased numbers of activated fibroblasts/myofibroblasts4. Subepithelial fibrosis5. 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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

J Allergy Clin Immunol 2007;120: 1233-44

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

Subepithelial layer thickening• increased deposition of extracellular matrix proteins

(ECMs)

• Subepithelial basement membrane thickening is confined to the lamina reticularis (reticular basement membrane - RBM)

Manuyakorn W,et al. APJAI 2013;31:3-10

The true basement membrane(lamina rara and lamina densa) is not altered in thickness in asthma

Subepithelial layer thickening• 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

Manuyakorn W,et al. APJAI 2013;31:3-10

Subepithelial layer thickening• Major cells (ECMs production) are fibroblasts,myofibroblasts• In an inflammatory environment

Manuyakorn W,et al. APJAI 2013;31:3-10

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

Manuyakorn W,et al. APJAI 2013;31:3-10

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

Manuyakorn W,et al. APJAI 2013;31:3-10

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

• 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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

Inflammation

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

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

Stephen T. Holgate, .Middleton’s Allergy 7’th edition ,893-915.

Epithelial loss

Reticular basement membrane thickness

Am J Respir Crit Care Med. 2008;178:476-82

Number of vessels

Eosinophils

Am J Respir Crit Care Med. 2008;178:476-82

IL-4+ cells

IL-5+ cells

Am J Respir Crit Care Med. 2008;178:476-82

All pathologic features examined were similar in nonatopic and atopic children

J Allergy Clin Immunol 2012;129:974-82

Severe therapy resistant asthma

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Airway remodeling

J Allergy Clin Immunol 2012;129:974-82

STRA Control

Eosinophilia

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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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

Epithelial injuryEnvironmental (pathogens, allergens, pollutants, and cigarette smoke)

or mechanical stress factors resulting in epithelial injury

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

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

Manuyakorn W,et al. APJAI 2013;31:3-10

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

Manuyakorn W,et al. APJAI 2013;31:3-10

N Engl J Med 2011;364:2006-15

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

Subepithelial layer thickening• 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

Manuyakorn W,et al. APJAI 2013;31:3-10

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

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

Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62

Am J Respir Crit Care Med. 2003;168:983-8

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

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

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

Manuyakorn W,et al. APJAI 2013;31:3-10

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

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

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 baselineData 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

Stephen T. Holgate, .Middleton’s Allergy 7’th edition ,893-915.

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

Thank you