1. PATHOLOGY OF BRONCHIAL ASTHMA

2. Bronchial Asthma o Describe types of bronchial asthma.
Define bronchial asthma.
o Describe types of bronchial asthma.
o Discuss etiopathogenesis of asthma.
o Describe morphological features.

3. Obstructive and restrictive lung diseases
Obstructive lung diseases
(i.e. increased resistance to air flow) include:-
1. Bronchial Asthma.
2. Emphysema.
3. Chronic bronchitis.
4. Bronchiectasis.
5. Cystic fibrosis and bronchiolitis.
Why should we care about asthma?

4. What is Asthma?
Definition:
Asthma is a chronic inflammatory disorder of the airways that causes recurrent spasmodic episodes, due to increased hyperirritability or responsiveness of the bronchial tree to various stimuli.
This associated with these clinical manifestations:
1. Wheezing.
2. Breathlessness.
3. Chest tightness.
4. Cough, particularly at night and/or in the early morning.
It is manifested physiologically by a widespread narrowing of the air passages, which may be relieved spontaneously or as a result of therapy. Can not cure but can controlled.
Life threatening disease
How long this episodes taking place? (Mild, severe) (Min\hr)

5. Bronchial asthma risk factors
1- Atopy (allergic asthma- largest risk factor- genetic).
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2 – Environmental factors( viruses, occupational exposures, allergens, cold air, dust, smoking ,others… ).
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3- family history.
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4- others……………..

6. Common triggers for asthma
Disease
characteristics

7. Bronchial asthma Classifications
Asthma may be categorized into types
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3- Bronchoconstriction triggering agents - include
( a) Seasonal asthma ( b) Exercise-induced asthma.
(c) Drug-induced asthma (e.g., aspirin & NSAID).
(d) Occupational asthma
(e) Eemotional asthma .
(f ) Asthmatic bronchitis in smokers.
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4-Recent studies added three subphenotypes of Asthma , based on Airway inflammation pattern.
1- Atopic type (allergic sensitization, Extrinsic).
2 - Non-atopic type (No allergic sensitization).

8. Asthma Types
1- Atopic asthma (allergic sensitization, Extrinsic) :
Classic example of type I IgE-mediated hypersensitivity reaction.
Usually encountered in patient known case of rhinitis, eczema.
Genetic predisposition.
A positive family history of asthma is common.
Begins in childhood.
Triggered by environmental allergens, such as dusts, pollens, roach or animal dander, and certain types of foods., etc…
Diagnosis: clinical diagnosis is essential +…………………………….
(a) Skin test : Using the offending antigen  immediate wheal-and-flare reaction.
(b) Serum radioallergosorbent tests (called RAST): TO identify the presence of IgE specific for a panel of allergens.

9. Asthma Types - Non allergic.
2. Non-atopic asthma:
- Non allergic.
- Triggered commonly  by Respiratory infection due to viruses (e.g., rhinovirus, parainfluenza virus).
- Family history: less common.
- Skin test: reveals negative reaction.
- Mechanism:
It is thought that virus-induced inflammation of the respiratory mucosa  lowers the threshold of the subepithelial vagal receptors to irritants.

10. Asthma Types 3- Bronchoconstriction triggering agents
(a) Drug-Induced Asthma.
- Aspirin-sensitive asthma + NSAID occurring with recurrent rhinitis and nasal polyps.
-Others examples: adrenergic antagonists, coloring agents .
Commonly occurs in adult.
Mechanism:
Aspirin inhibiting the cyclooxygenase pathway of arachidonic acid metabolism without affecting the lipoxygenase route, thus tipping the balance toward elaboration of the bronchoconstrictor leukotrienes.

11. Asthma Types (b) Occupational Asthma.
Caused or worsened by breathing in irritants on the job. 
Triggered\stimulated by:
1) Fumes (epoxy resins, plastics)
2) Metal and dusts (platinum, wood, cotton)
3) Chemicals and Gases (formaldehyde, penicillin products, toluene, enzymes).
4) Animal substances (5) Plants
- Minute quantities & Repeated exposure.
- Mechanisms:
According to stimulus include:-
Type I hypersensitivity reactions .
Liberation of bronchoconstrictor substances.
Hypersensitivity responses of unknown origin.

12. Bronchial asthma Recent studies
4- Pattern of the Airway inflammation :
1) Eosinophilic asthma.
2) Neutrophilic asthma.
3) Mixed inflammatory asthma.
4) Pauci-granulocytic asthma.
These subgroups may differ in their:
(a) Etiology.
(b) Immunopathology.
(c ) Response to treatment.
Recent studies

13. Asthma Pathogenesis-1 GENETIC CONSIDERATIONS Genetic predisposition
In case of Atopic asthma- type I hypersensitivity
Inheritance of susceptibility genes (postulation) that makes individuals prone to develop strong TH2 reactions against environmental antigens (allergens)

14. Asthma Pathogenesis-2
1. The airway epithelium and submucosa contain dendritic cells that capture &process antigen \allergens.
Initial sensitization  stimulate induction of TH2 cells.
2. TH2 cells secrete cytokines e.g.(IL-4, IL-5,IL-13) that promote allergic inflammation and stimulate B cells to produce IgE and other antibodies.
3. Action of Cytokins
(a) IL-4 Production of IgE by B cells.
(b)IL-5  Activates recruited eosinophils.
(c ) IL-13 Mucus secretion(bronchial submucosal glands)
 also Promotes IgE production by B cells.

16. Asthma Pathogenesis-3 (Early & Late reaction)
3. IgE coats submucosal mast cells.
4. Repeat exposure triggers the mast cells to release granule contents and produce cytokines and other mediators induce the early-phase (immediate hypersensitivity) reaction and the late-phase reaction

17. Asthma Pathogenesis-4 (Early reaction- Minutes)
- AntigensTh2+ IgE productionIgE binding to mast cells leads to Eosp. recruitment& release of primary mediators=
(Histamine, chemotactic factors, and secondary mediators i.e. leukotriens, prostaglandins, cytokines and neuropeptides). This results in:
(A) Bronchospasm- triggered by direct stimulation of subepithelial vagal (parasympathetic) receptors through both central and local reflexes .
(B) Secretion of mucus.
(C) Variable degree of vasodilatation& increase permeability.
(D) Accumulation of leukocytes.

18. Asthma Pathogenesis-5 (Late reaction- Hours)
hr later, produces a continued state of airway
hyperresponsiveness with eosinophilic and neutrophilic infiltration. (steroid helpful to treat this stage)
Components: consists largely of inflammation with recruitment of leukocytes= ( Eosinophils, neutrophils, and more T cells).
- Leukocyte recruitment is stimulated by chemokines produced by mast cells, Epithelial cells (eotaxin ) and T cells, and by other cytokines.
- Outcome: persistent bronchospasm, edema, and necrosis of epithelial cells by The major basic protein of eosinophils.

19. Cellular sources of inflammatory mediators& their effects
Cells
Bronchoconstriction
Plasma exudation
vasodilatation
Mucus hypersecretion
Structural changes
(fibrosis, smooth
hyperplasia,
angiogenesis, mucus
hyperplasia)
Destroying the airway epithelium
Histamine
Endothelin-1
Leukotrienes
Prostaglandins
Thromboxane
Bradykinin
Tachykinins
Reactive oxygen
species
Adenosine
Anaphylatoxins
Endothelins
Nitric oxide
Cytokines
Growth factors
Mast cells
Macrophages
Eosinophils
T lymphocytes
Epithelial cells
Fibroblasts
Neurons
Neutrophils
Platelets?
Basophils?

20. Atopic asthma Epithelial cell injury Allergen IgE Mucus secretion
Muscle contraction
Mast cell
Muscle contraction
Release of inflammatory mediators
Recruitment of leukocytes
Acute phase
Late-phase

21. Morphology of Asthma -
- Gross appearance: - Done in lungs necropsy-study
1. Over-inflated and failure to collapse with patchy atelectasis (pt. dying with Status asthmaticus).
2. Occlusion of airways by gelatinous mucous & exudate
plugs (the bronchial branches up to terminal bronchioles)
Microscopic appearance:
Edema, hyperemia, and inflammatory infiltrate (with excess eosinophils) in the bronchial walls.
Increase in the size of submucosal glands (hypertrophy\ hyperplasia)
Patchy necrosis and shedding of epithelial cells.
Over time – features of airway remodeling.

22. Airway remodeling.
Overall thickening of airway wall . Reduction of diameter
Basement membrane fibrosis(BM thickening).
Increases muscle mass (Hypertrophy and/or hyperplasia).
Increased in size and number of blood vessels.
Increase number of the submucosal glands.
Mucus metaplasia of epithelium.
Increased fibrogenic factors collagen type I,II “scar”
Irreversible Airflow obstruction.

23. Epithelial remodeling
CONTROL
Lamina propia is a thin layer of loose connective tissue which along with epithemliun forms the mucosa. It contains cappilaries and mucosal cells that secrete mucous.
Epithelium is damaged
New blood vessels
New muscle
New mucosal cells
Collagen deposition 23 23 23

26. Bronchial asthma, microscopic

27. Investigating asthma
1. Elevated eosinophil count in the peripheral blood &CBC.
2. Sputum smear- Whorled mucous plugs = Curschmann spirals.
3. Sputum smear- Charcot-Leyden crystals in the sputum (Specially in atopic asthma). (Sputum).
4. Sputum -Creola bodies (desquamated epithelial cells)
5. Skin Test
6. RAST test.
used to monitor a person's ability to breathe out air.
Reduced when airways are constricted.
Whorled mucous plugs (Curshman’s spiral)
Crystalloid debris of eosinophil-protein (Charcot-Leyden crystals): collections of crystalloid made up of an eosinophil lysophospholipase binding protein called galectin.

28. Curschman’s spirals

29. Charcot-Leyden crystals

30. THE END