Asthma Pathophysiology N

1. ?!*$#
““Twenty years from nowTwenty years from now
you will be more disappointedyou will be more disappointed
by the things you by the things you didn'tdidn't do do
than by those you did.”than by those you did.”
...Catch the trade winds in your sails, ...Catch the trade winds in your sails,
explore, dream, discover & explore, dream, discover & live….! ” live….! ”
- Mark Twain

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Asthma Asthma
PathophysiologyPathophysiology
Dr. Venkatesh M. Shashidhar.
Senior Lecturer in Pathology
Fiji School of Medicine

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AsthmaAsthma::
Chronic Chronic InflammatoryInflammatory disorder of bronchi disorder of bronchi
characterized bycharacterized by EpisodicEpisodic, , reversiblereversible
bronchospasmbronchospasm resulting from an resulting from an
exaggerated bronchoconstrictor response exaggerated bronchoconstrictor response
to various stimuli (to various stimuli (allergyallergy) )
Affects 10% of children & 5%-7% adultsAffects 10% of children & 5%-7% adults

Highest in NZ, Highest in NZ, Low in Fiji ~ 1%Low in Fiji ~ 1% ©©

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Asthma Facts ?Asthma Facts ?
Asthma is “all in the mind.” Asthma is “all in the mind.”
You will “grow out of it.” You will “grow out of it.”
Asthma can be cured, Asthma can be cured,
Not very serious disease and nobody dies from it. Not very serious disease and nobody dies from it.
You are likely to develop asthma if someone in your You are likely to develop asthma if someone in your
family has it. family has it.
You can “catch” asthma from someone else who has it. You can “catch” asthma from someone else who has it.
Moving to a different location can cure asthma. Moving to a different location can cure asthma.
People with asthma should not exercise. People with asthma should not exercise.
Asthma does not require medical treatment. Asthma does not require medical treatment.
Medications used to treat asthma are habit-forming. Medications used to treat asthma are habit-forming.
Someone with asthma can provoke episodes anytime.Someone with asthma can provoke episodes anytime.
Asthma can spread to other persons through caughing.Asthma can spread to other persons through caughing.
Asthma is born with you. Familial/genetic.Asthma is born with you. Familial/genetic.

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Percent Change in Age-Adjusted Percent Change in Age-Adjusted
Death Rates, U.S., 1965-1998Death Rates, U.S., 1965-1998
0
0.5
1.0
1.5
2.0
2.5
3.0
Proportion of 1965 Rate
1965 - 19981965 - 19981965 - 19981965 - 19981965 - 1998
–59% –64% –35% +163% –7%
Coronary
Heart
Disease
Stroke Other CVD COPD All Other
Causes

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INFLAMMATIONINFLAMMATION
Airflow Limitation
SYMPTOMS
Cough Wheeze
Dyspnoea
TRIGGERS
Allergens, Exercise,
Cold Air, SO2 Particulates
Pathogenesis:Pathogenesis:
Airway
Hyperresponsiveness
Genetic*
INDUCERS
Allergens,Chemical sensitisers,
Air pollutants, Virus infections

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Asthma Pathogenetic Types:Asthma Pathogenetic Types:
Extrinsic (Allergic/Immune)Extrinsic (Allergic/Immune)
Atopic - IgEAtopic - IgE
Occupational - IgGOccupational - IgG
A. Bronchopulomonary Aspergillosis - IgEA. Bronchopulomonary Aspergillosis - IgE
Intrinsic (Non immune)Intrinsic (Non immune)
Aspirin inducedAspirin induced
Infections inducedInfections induced

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Pathogenesis - Atopic Asthma:Pathogenesis - Atopic Asthma:

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Mast cells in Asthma Pathogenesis:Mast cells in Asthma Pathogenesis:

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Eosinophils in Asthma Pathogenesis:Eosinophils in Asthma Pathogenesis:

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Lung Morphology in AsthmaLung Morphology in Asthma
Bronchial inflammationBronchial inflammation
Edema, MucouspluggingEdema, Mucousplugging
BronchospasmBronchospasm
ObstructionObstruction
Over inflation/AtelectasisOver inflation/Atelectasis
COPDCOPD

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Lung Hyperinflation in AsthmaLung Hyperinflation in Asthma

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Thick bronchi with Mucous plugsThick bronchi with Mucous plugs

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Mucous plug in asthma:Mucous plug in asthma:

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Asthma - MicropathologyAsthma - Micropathology
Patchy Patchy necrosisnecrosis of epithelium of epithelium
Sub-mucosal Sub-mucosal glandularglandular hyperplasiahyperplasia
Hypertrophy of bronchial Hypertrophy of bronchial smoothsmooth musclemuscle
EosinophilsEosinophils, , mastmast cellscells; ; lympholympho (TH2, CD4) (TH2, CD4)
Mucous Mucous plugsplugs, Curschmann spirals,, Curschmann spirals,
Charcot Layden crystals.Charcot Layden crystals.

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Asthma Microscopic PathologyAsthma Microscopic Pathology
Obstructed
Inflammed
Bronchi

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Asthma - Bronchial morphologyAsthma - Bronchial morphology
inflammation inflammation
EosinophilsEosinophils
Gland hyperplasiaGland hyperplasia
Mucous plug in Mucous plug in
lumenlumen
Hypertrophy of Hypertrophy of
muscle layermuscle layer

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Asthma - Bronchial morphologyAsthma - Bronchial morphology
InflammationInflammation
Mucous PlugMucous Plug
EosinophilsEosinophils

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Asthma – TH2 lymphocytesAsthma – TH2 lymphocytes
immunostaining)immunostaining)

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Eosinophils in Asthma:Eosinophils in Asthma:

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Curschmann's spirals:Curschmann's spirals:

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New Pathology & Drugs in Asthma:New Pathology & Drugs in Asthma:
Leukotriences - significant role in AsthmaLeukotriences - significant role in Asthma
Mast cells and Eosinophil - Mast cells and Eosinophil - CytokinesCytokines. .
Arachidonic acid - Arachidonic acid - Lipo-oxygenaseLipo-oxygenase – – LTD4LTD4
Bronchospasm – Bronchospasm – Cys-LT1Cys-LT1 receptor receptor
ZileutonZileuton – Lipoxygenase inhibitor – Lipoxygenase inhibitor
MontelukastMontelukast & & zafirlukastzafirlukast - inhibit CysLT1 - inhibit CysLT1

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Arachidonic Acid
Leukotrienes
LTC4, D4, E4
Cyclooxygenase5-Lipoxygenase
Prostaglandins
Prostacyclins
Cell Damage
Cell Membrane
Phospholipids
5-LO inhibitors
Antileukotrienes
Steroids
NSAID

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History of Leukotrienes:History of Leukotrienes:
Samuelsson et al. (1979) Stockholm found Samuelsson et al. (1979) Stockholm found
arachidonic acid metabolites in arachidonic acid metabolites in
anaphylaxis, (SRS) called them anaphylaxis, (SRS) called them
"leukotrienes.“ now known to be cysteinyl "leukotrienes.“ now known to be cysteinyl
leukotrienes (LT-C4, D4 and E4).leukotrienes (LT-C4, D4 and E4).
* Samuelsson later won the * Samuelsson later won the Nobel PrizeNobel Prize

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The Reality The Reality 
Asthma is not yet curable *Asthma is not yet curable *
Underdiagnosis & UndermanagementUnderdiagnosis & Undermanagement
Therapy is still evolvingTherapy is still evolving
Hope Hope 
Better understanding of Better understanding of PathologyPathology
New line of Promissing Drugs.New line of Promissing Drugs.
Proper management Proper management  normal life. normal life.

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Thank You…Thank You…
Dr. Venkatesh M. Shashidhar.
Senior Lecturer in Pathology
Fiji School of Medicine

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Asthma Pathology - Modern view
Barnes PJ
Allergen
Mucus
hypersecretion
Hyperplasia
Vasodilatation
New vessels
Plasma leak
Oedema
Bronchoconstriction
Hypertrophy/hyperplasia
Cholinergic
reflex
Subepithelial
fibrosis
Sensory nerve
activation
Eosinophil
Mast cell
Th2 cell
Neutrophil
Macrophage/
dendritic cell
Mucus plug
Epithelial shedding
Nerve activation
Leukotrienes
C4, D4 & E4

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Mast cell Degranulation
Barnes PJ
Normal 5 Seconds 60 Seconds

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Mast cell Degranulation
Barnes PJ

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Type I Hypersensitivity:
Barnes PJ

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Therapy - Pathology:
Barnes PJ