1. Asthma is a chronic inflammatory disorder of the bronchi characterized by episodic and reversible bronchospasm caused by an exaggerated response to various stimuli like allergens. 2. It affects 10% of children and 5-7% of adults worldwide. The pathogenesis involves inflammation, airflow limitation, and airway hyperresponsiveness triggered by allergens, viruses, pollutants, and other factors. 3. New understanding of the role of leukotrienes, mast cells, eosinophils and cytokines in asthma pathology has led to more targeted drug therapies that inhibit these inflammatory pathways.

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

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

3. Asthma : Chronic Inflammatory disorder of bronchi characterized by Episodic , reversible bronchospasm resulting from an exaggerated bronchoconstrictor response to various stimuli ( allergy ) Affects 10% of children & 5%-7% adults Highest in NZ, Low in Fiji ~ 1% 

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

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

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

7. Asthma Pathogenetic Types: Extrinsic (Allergic/Immune) Atopic - IgE Occupational - IgG A. Bronchopulomonary Aspergillosis - IgE Intrinsic (Non immune) Aspirin induced Infections induced

8. Pathogenesis - Atopic Asthma:

9. Mast cells in Asthma Pathogenesis:

10. Eosinophils in Asthma Pathogenesis:

11. Lung Morphology in Asthma Bronchial inflammation Edema, Mucousplugging Bronchospasm Obstruction Over inflation/Atelectasis COPD

12. Lung Hyperinflation in Asthma

13. Thick bronchi with Mucous plugs

14. Mucous plug in asthma:

15. Asthma - Micropathology Patchy necrosis of epithelium Sub-mucosal glandular hyperplasia Hypertrophy of bronchial smooth muscle Eosinophils , mast cells ; lympho (TH2, CD4) Mucous plugs , Curschmann spirals, Charcot Layden crystals.

16. Asthma Microscopic Pathology Obstructed Inflammed Bronchi

17. Asthma - Bronchial morphology inflammation Eosinophils Gland hyperplasia Mucous plug in lumen Hypertrophy of muscle layer

18. Asthma - Bronchial morphology Inflammation Mucous Plug Eosinophils

19. Asthma – TH2 lymphocytes immunostaining)

20. Eosinophils in Asthma:

21. Curschmann's spirals:

22. New Pathology & Drugs in Asthma: Leukotriences - significant role in Asthma Mast cells and Eosinophil - Cytokines . Arachidonic acid - Lipo-oxygenase – LTD4 Bronchospasm – Cys-LT1 receptor Zileuton – Lipoxygenase inhibitor Montelukast & zafirlukast - inhibit CysLT1

23. 5-LO inhibitors Antileukotrienes Arachidonic Acid Leukotrienes LTC4, D4, E4 Cyclooxygenase 5-Lipoxygenase Prostaglandins Prostacyclins Cell Damage Cell Membrane Phospholipids Steroids NSAID

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

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

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

27. Asthma Pathology - Modern view Barnes PJ Leukotrienes C4, D4 & E4 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

28. Mast cell Degranulation Barnes PJ Normal 5 Seconds 60 Seconds

29. Mast cell Degranulation Barnes PJ

30. Type I Hypersensitivity: Barnes PJ

31. Therapy - Pathology: Barnes PJ