Asthma Pathophysiologyn 1233730055155655 1

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Asthma Asthma PathophysiologyPathophysiology

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AsthmaAsthma::

Chronic Chronic InflammatoryInflammatory disorder of disorder of bronchi characterized bybronchi characterized by EpisodicEpisodic, , reversiblereversible bronchospasmbronchospasm resulting from resulting from an exaggerated bronchoconstrictor an exaggerated bronchoconstrictor response to various stimuli (response 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-Percent Change in Age-Adjusted Death Rates, U.S., Adjusted Death Rates, U.S., 1965-19981965-1998

Percent Change in Age-Percent Change in Age-Adjusted Death Rates, U.S., Adjusted Death Rates, U.S., 1965-19981965-1998

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

Proportion of 1965 Rate Proportion of 1965 Rate

1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998

–59%–59% –64%–64% –35%–35% +163%+163% –7%–7%

CoronaryHeart

Disease

CoronaryHeart

Disease

StrokeStroke Other CVDOther CVD COPDCOPD All OtherCauses

All OtherCauses

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INFLAMMATIONINFLAMMATIONAirflow Limitation

SYMPTOMSCough Wheeze

Dyspnoea

TRIGGERS Allergens, Exercise,

Cold Air, SO2 Particulates

PathogenesiPathogenesis:s:

AirwayHyperresponsiveness

Genetic*

INDUCERSAllergens,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 - A. Bronchopulomonary Aspergillosis -

IgEIgE Intrinsic (Non immune)Intrinsic (Non immune)

Aspirin inducedAspirin induced Infections inducedInfections induced

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Pathogenesis - Atopic Pathogenesis - Atopic Asthma:Asthma:

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

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Eosinophils in Asthma Eosinophils in Asthma Pathogenesis:Pathogenesis:

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Lung Morphology in AsthmaLung Morphology in Asthma

Bronchial Bronchial inflammationinflammation

Edema, Edema, MucouspluggingMucousplugging

BronchospasmBronchospasm ObstructionObstruction Over Over

inflation/Atelectasisinflation/Atelectasis COPDCOPD


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Lung Hyperinflation in AsthmaLung Hyperinflation in Asthma


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Thick bronchi with Mucous Thick bronchi with Mucous plugsplugs


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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, (TH2,

CD4) CD4) Mucous Mucous plugsplugs, Curschmann spirals,, Curschmann spirals, Charcot Layden crystals.Charcot Layden crystals.


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Asthma Microscopic Asthma Microscopic PathologyPathology

ObstructedInflammedBronchi


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Asthma - Bronchial morphologyAsthma - Bronchial morphology

inflammation inflammation EosinophilsEosinophils Gland Gland

hyperplasiahyperplasia Mucous plug in Mucous plug in

lumenlumen Hypertrophy of Hypertrophy of

muscle layermuscle layer


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Asthma - Bronchial morphologyAsthma - Bronchial morphology

InflammatioInflammationn

Mucous Mucous PlugPlug

EosinophilsEosinophils


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Asthma – TH2 lymphocytesAsthma – TH2 lymphocytesimmunostaining)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 New Pathology & Drugs in Asthma:Asthma:

Leukotriences - significant role in Leukotriences - significant role in AsthmaAsthma

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 - inhibit

CysLT1CysLT1


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Arachidonic Acid

Leukotrienes

LTC4, D4, E4

Cyclooxygenase

5-Lipoxygenase

Prostaglandins

Prostacyclins

Cell Damage

Cell Membrane Phospholipids

5-LO inhibitorsAntileukotrienes

Steroids

NSAID


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History of Leukotrienes:History of Leukotrienes:

Samuelsson et al. (1979) Stockholm Samuelsson et al. (1979) Stockholm found arachidonic acid metabolites in found arachidonic acid metabolites in anaphylaxis, (SRS) called them anaphylaxis, (SRS) called them "leukotrienes.“ now known to be "leukotrienes.“ now known to be cysteinyl leukotrienes (LT-C4, D4 and cysteinyl leukotrienes (LT-C4, D4 and E4).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 & Underdiagnosis &

UndermanagementUndermanagement 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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Asthma Pathology - Modern Asthma Pathology - Modern viewview

Barnes PJ

Allergen

MucushypersecretionHyperplasia

VasodilatationNew vessels

Plasma leak Oedema

BronchoconstrictionHypertrophy/hyperplasia

Cholinergic reflex

Subepithelialfibrosis

Sensory nerve activation

Eosinophil

Mast cell

Th2 cell Neutrophil

Macrophage/dendritic cell

Mucus plugEpithelial shedding

Nerve activation

LeukotrienesC4, D4 & E4


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Mast cell DegranulationMast cell Degranulation

Barnes PJ

Normal 5 Seconds 60 Seconds


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Mast cell DegranulationMast cell Degranulation

Barnes PJ


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Type I Hypersensitivity:Type I Hypersensitivity:

Barnes PJ


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Therapy - Pathology:Therapy - Pathology:

Barnes PJ


Shashi

THANK YOU THANK YOU

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Asthma Pathophysiologyn 1233730055155655 1