Asthma Pathogenesis

Topic included..
 Pathology of asthma
 Anatomical change
 Multicellular inflammation
 Which are factors contributed to asthma
pathogenesis (Filaggrin , TLSP, TARC,..?)
 Distinct type of asthma : neutrophilic
inflammation

Asthma
 A disorder of the conducting airways
 Through variety of provocation (different
pathways)…produce the same result of
 Airway hyperesponsiveness :
 Contract too much, too easily spontaneously and
in response to exogenous/endogenous stimuli
 Variable airflow obstruction
 Multi-cellular inflammation

Stephen T. Holgate.Clin Exp Aller 2008:38;872-97

Pathology
 Epithelial desquamation
 Thickening of lamina reticularis
 Increased numbers of
myofibroblasts
 Evidence of airway remodeling
 Hypertrophy and hyperplasia of
airway smooth muscle
 Mucous gland hyperplasia
 Angiogenesis

Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915

Stephen Holgate.JACI 2007:120;1233-44

Normal airway epithelium compared with mildly symptomatic atopic asthma

Picture from Middleton

The reason for that..
1. Fragility of epithelium
2. Defective of repairment
3. Tight junctions cannot fully developed
4. Loss of antioxidant function
5. Cytokines that damaged epithelium

Increase destruction :
Fragility of epithelium
 More severe in allergic than non-allergic forms
 Greater loss : greater degree of airway
responsiveness
 Reduced with glucocorticoid therapy
 Creola bodies

 Epithelial cells from asthmatic airways, are
unable to form effective TJs fully measurement
of transepithelial resistance indicating increased
leakiness


Plane of separation between
columnar and basal cells: Creola bodies: slough
disruption of desmosomal linkages clumps of epithelial cells


Immunofluorescence with antibodies directed to ZO-1
and occludin confirmed poorly developed TJs in
asthmatic compared with normal cultures


Filaggrin

2008;122:
689-93

Regan et al.JACI 2008;122:689-93

At least in a subset of those with asthma, the filaggrin
gene defect may be the fundamental predisposing factor
not only for the development of eczema but also asthma

Expose to Injurious agents &
allergens: disrupted TJs

Tobacco smoke extract
Respiratory viruses
Proteolytically active allergens eg.Der p1
Oxidants (can break perijunctional actin)


Expose to Injurious agents &
allergens: other mechanisms

 Some chemical and biological agents insult tissue
damaging through the generation of reactive oxygen
species
 Lack some of antioxidative capacity (Comhair SA et al.2007)
 superoxide dismutase and glutathione peroxidase

 Enhanced release of proinflammatory cytokines in
response to diesel exhaust particle exposure


Int Arch Allergy Immunol 1999;118:437–439

Defective repair of epithelium
 Normal patients : mitotic activity in remaining epithelial cells by
regeneration of normal ciliated and goblet cells : entired process
2 wks!

 By stimulate intrinsic repair pathways with engagement of EGFRs
by autocrine secretion of appropriate EGF family eg. EGF, heparin-
binding EGF-like growth factor to drive cell migration, proliferation

 Asthmatic epithelial cells : reduced expression of proliferative
markers such as Ki67 (nuclear expression of cell cycle markers)
and upregulation of cell cyclin inhibitor,nuclear p21wat


Asthmatic patients : repair by simple, stratified
squamous epithelium or goblet cells

Airway Epithelium
 As fragility and impaired proliferation; the epithelium
is chronically injuried and unable to repair properly

 Leakiness of epithelium leading to greater access of
inhaled allergens, pollutants and irritants

 Consider asthma as a disease of impaired barrier
function

 Next assessment : gene regulation comparing asthmatic
with normal epithelial cells

Stephen Holgate.Clin Exp Allergy 2008:38;872-97

Epithelial cells: as an effector cells
 Physiochemical barrier

 Regulated recruitment, activation and differentiation of
inflammatory cells in response to exogenous stimuli that
cause epithelial damage from those cells remain
 Upregulated expression of ICAM-1
 Proinflammatory cytokines (IL-1ß, TNF-α, IL-6)
 Cytokines (GM-CSF, G-CSF, IL-4, -13,-9, -5, -10, -11, -16,
TGFß)
 Peptide mediators – endothelin-1 and -3 (bronchoconstriction)


Chemokines
 CXC or α Chemokines
 ELR (Glu-Leu-Arg) containing CXC :
predominantly chemoattractant for neutrophils
 Non-ELR CXC : induced by IFN
 CC or ß chemokines : chemoattractants for
eosinophils, basophils, monocytes,
dendritic cells, lymphocytes

IL-8 (CXCL8) Potent chemoattractant of neutrophils

Eotaxin (CCL11) Chemoattractant of eosinophils = CCR3

RANTES (CCL5) Predominant chemoattractant of eosinophils

TARC (CCL17) Chemoattractant for Th2 lymphocytes = CCR4

Thymic stromal lymphopoietin is releasedby human epithelial
cells in responseto microbes, trauma, or inflammation
and potently activates mast cells

Allakhverdi et al.JEM 2003:204(2);253–258

A Novel Cytokine : TSLP

Stephen T. Holgate.JACI 2007;120:1233-44

A Novel Cytokine : TSLP
 TSLP : IL-7 like cytokine
 Correlations between TSLP expression, TARC/
CCL17,MDC/CCL22
 Th2-polarization is more closely under the control
of TSLP at the epithelium where the airways inter
act with the environment
 Altered responses to this interaction in asthmatics
may reflect inherent abnormalities of the
epithelium itself, such as altered responses to vira
l infection

Ying et al.J Immunol 2005;174:8183–90

The bronchial epithelium is highlighted as
a key site for asthma pathogenesis

Stephen T. Holgate.
JACI 2007;120:1233-44

Hyalinization and thickening of
lamina reticularis

RBM


Basal membrane
 Initiated close to disease onset
 The extent of thickness does not relate to severity,
duration, fatality, responsiveness to control and
does not progressive

 Basal lamina (true basement membrane)
 Lamina reticularis/ reticular basement membrane


Lamina Reticularis
 Found only in humans and primates
 Reticulin fibers (collagen type I, III, VI), tenascin, heparin
sulfate and serum-derived components
 Homogenous hyaline in appearance
 Myofibroblast numbers beneath RBM correlating with
extent of collagen thickness
 Relate with epithelial secreting EGF familiy agents after
epithelial injury


Smooth muscle
 Hyperplasia : larger airways (more characterized)
 Hypertrophy : smaller airways
 Cause from continuous irritation by mediators, repeated
episodes of bronchoconstriction, loss of inhibitory
control with unopposed myogenic activity, EGF can
induce airway smooth muscle mitogenesis
 Correlate with fatal asthma more than long-standing
process
 Increase muscle mass : marked increase resistence to
airway flow that may become life threatening


Mucous secreting elements
 Submucosal gland enlargement and goblet cell
hyperplasia : histological hallmarks
 Numbers of goblet cells that secrete viscus mucus
increases, with a parallel reduction in cilated cells
 Goblet cells occurred in the more peripheral airways which
are normally devoid of goblet cells
 IL-4, IL-9, IL-13, TNF-α EGF play a significant role
 Mucus (adhere and continuity with goblet cell apex) mixed
with inflammatory exudative plugs in the airways in fatal
asthma


ST Holgate. Clin Exp Allergy 2008;38:872-97

Cellular Infiltration
 Multicellular process :
 Eosinophils (mainly)
 Neutrophils Recruited from circulation
 CD4+ T lymphocytes
 Mast cells : activated resident cells in airways
 Macrophages and dendrtitic cells : both resident
cells and recruitment to the lung
 NKT cells??


Mast cells
 Mucosal mast cells : Tryptase MCs
 Connective tissue mast cells : Chymase tryptase MCs

 Histamine, PGD2, LTC4 : induce bronchoconstriction
mucous secretion, mucosal edema
 Cytokines (IL-4, IL-5, IL-13) : IgE synthesis, Th2
differentiation, eosinophilic inflammation
 TNF-α, TGF-ß, FGF, tryptase, chymase - activated
fibroblasts : airway remodelling


Mast cells
 Microlocalization of mast cells is a critical event in
development of asthmatic phenotype
 Airway smooth muscle TC mast cells infiltration in
asthma, not in eosinophilic bronchitis : enhanced
contractility
 Also contributing to fibrogenesis and an increase
in smooth muscle “remodelling response”


Mucosal layers Submucosal layers

NEJM 2002;346:1699-705

Interaction between mast cells
and airway smooth muscle
 SCF (c-kit ligand) : produced by epithelium, smooth
muscle, fibroblasts
 CXCL8/CXCL10 produced by airway smooth muscle
interact with CXCR3/CXCR2 on mast cells (recruitment,
enhanced mediator secretion)

 Reverse reaction : mast cells secrete CCL19, stimulate
airway smooth muscle through CCR7 stimulate muscle
migration and contribute to smooth muscle hyperplasia


Eosinophils
• Very prominent cell
in allergic asthma
• IL-3, GM-CSF, eotaxin
: early derivation
• IL-5 : maturation and
recruitment into the
airways

Trivedi and Lloyd.Cell. Mol.
Life Sci. 2007:64;1269 – 89

Trivedi and Lloyd.Cell. Mol. Life Sci. 2007:64;1269 – 8

Alveolar macrophages and dendritic cells
 The most numerous cells in the airway
lumen in normal and asthma patients
 2 important roles
 Inflammatory cytokines
 Proinflammatory cytokines :MIP-1α (CCL3), TNF-
α, GM-CSF
 Chemokines : CXCL8, CCL5, CCL11
 Eicosanoids : prostaglandins, LTB4


Alveolar macrophages and dendritic cells
 Anti-inflammatory cytokines : IL-10
 Th1 cytokines : IL-12
 Th2 cytokines : CCL17 and CCL22 in response to
allergen challenge

 Role as APCs when interact with local inflammatory
cytokines eg. TSLP : Th2 polarization


Lymphocytes
 Severity of asthma can be reflected by the activation
stage; CD25
 Th2 cytokines :center role in secreting IL-4, IL-5, IL-13
 Th1/Th2 imbalance should not be viewes as
pathognomonic for asthma
 Th1 shift does not lead to fewer asthma symptoms
 In severe asthma, we found elevation levels of IFN-Ɣ in
serum and BAL fluid
 Role of T-regulatory cells?? : little evidence


Neutrophils
 Commonly found in airway of healthy patients
 Neutrophilic asthma
 During viral induced exacerbations

 Role in asthma is still undefined
 Reflect of disease severity?
 A consequence of corticosteroid treatment


Neutrophils mediate asthma pathogenesis
through…
1. Potent proinflammatory functions : TNF-α, IL-1,
IL-8, GM-CSF, G-CSF
2. Innate immune activation
 Epithelium of neutrophilic asthma express higher levels
of TLR2,4, CD 14 and surface protein A which may
occur in response to increase in airway endotoxin,
bacterial colonization and respiratory viruses
3. Role in airway remodeling via capacity of
release TGF-ß, VEGF (in asthmatic patients)


Heterogenity of asthma; according to
BAL
 Eosinophilic asthma
 Neutrophilic asthma
 Mixed inflammatory
asthma
 Paucigranulocytic
asthma

Neutrophillic asthma
 Patients who die sudden from asthma, severe asthma,
corticosteroid dependent

 Tends to be older and a more aggressive disease with
more tissue destruction and airway remodelling

 Similar in terms of gender, atopy, smoking and lung
function

 Distinct immune and inflammatory mechanisms
involving innate immune dysfunction


Neutrophillic asthma
 In response to involving pathogens; epithelial signals
were sent to recruit inflammatory cells

 If the responses are not insufficient to eliminate
microbes; chronic persistent inflammation occurred and
can damage host tissue

 Evidence that innate immunity was stimulated
 Endotoxin levels esp. from H. influenza and
P. aeruginosa were increased


Take Home Message
 Asthma is a heterogenous disease which has the
same manifestations of
 Airway hyperesponsiveness :
 Variable airflow obstruction
 Multi-cellular inflammation
 Epithelium seems to be a key regulator of asthma
 Filaggrin gene polymorphisms have increased
risks of developing asthma in atopic eczema
patients

Take Home Message
 Pathology
 Epithelial disruption : Creola bodies
 Homogenous thickening of lamina reticularis
 Airway remodelling
 Mast cells infiltrated at airway smooth muscle
 TARC and TSLP : Th2 polarization
 To know more about asthma pathogenesis could
contribute to know the target points of treatment

Asthma Pathogenesis

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Asthma Pathogenesis