1. ASTHMA
PATHOLOGY,PATHOGENESIS
Dr.Amith Sreedharan
DEPT OF PULMONARY MEDICINE
SCB MCH , CUTTACK

2. DEFINITION
• A chronic inflammatory disorder of the airways in
which many cells and cellular elements play a role.
• The chronic inflammation is associated with airway
hyperresponsiveness that leads to recurrent episodes
of wheezing,breathlessness,chest tightness and
coughing,particularly at night or in the early morning.
• These episodes are usually associated with widespread
but variable,airflow obstruction within the lung that is
often reversible either spontaneously or with
treatment

3. • 300 million affected individuals
• 1% -18% - global prevalence
• 15 million DALY – global burden

4. GENETICS
 Higher concordance in Monozygotic twins
 ↑ed incidence in primary relatives
• ADAM-33 1st gene identified as Asthma susceptibility gene
• 10 most common genes a/w Asthma
 Innate immunity (CD-14,HLA DRB1,DQB1)
 Th₂ cell signalling (IL-4,IL-13,IL-4Ra)
 Cellular inflammation (TNF,FCEDR1B)
 Lung development (ADAM33,ADRB2)
 GWAS : 17 q 21,11 p 14,5 q 23,Chr 18
 Environment : Epigenetic modifications

5. ATOPIC ASTHMA
Begins in childhood.
A positive family history of atopy is common,
Asthmatic attacks are often preceded by allergic
rhinitis, urticaria, or eczema.
The disease is triggered by environmental
antigens, such as dusts, pollen, animal dander, and
foods, but potentially any antigen is implicated.
A skin test with the offending antigen results in an
immediate wheal-and-flare reaction, a classic
example of the type I IgE-mediated
hypersensitivity reaction .

7. MODELS OF MECHANISMS OF ASTHMA
• LATE PHASE ASTHMATIC RESPONSE MODEL
Inhalation of allergen
Acute phase response – immediate onset
Wheezing,cough,SOB
Resolves within 1 hour
Late phase response
4-6 hours after allergen challenge
Persists for 24- 48 hours
Isolated LPR rare,seen in Occupational Asthma

8. • Late asthmatic reactions ̴ chronic asthma
• Increased airway responsiveness
• Decreased response to BD therapy
• Bronchial inflammation
• Asthma pts,with Dual phase: LPR prolonged
and intense
• Previously Airway Eosinophilia,now Basophil
levels correlate with LPR
• APR BAL:histamine,tryptase,PGD₂(mast cell)
• LPR BAL :histame,tryptase no PGD₂(basophil)
• Basophil: release Th₂ cytokines IL-4,IL-5,IL-13

10. Respiratory viruses and asthma
• Respiratory syncitial virus,Rhino virus
• Airaway hyperresponsiveness is increased
• Persist as long as 4 weeks
• Acute neutrophilic reponse
• Potentiates eosinophilic airway inflammation
• ↑ production of IL-8,GM-CSF,INFᵞ ,RANTES
• Modulate airway environment,components of
inflammation(cells and mediators)

11. NON ATOPIC ASTHMA
• The mechanism of bronchial inflammation and hyper-
responsiveness is much less clear in individuals with non-atopic
asthma.
• viral infections of the respiratory tract (most common) and
inhaled air pollutants such as sulfur dioxide, ozone, and nitrogen
dioxide.
• In asthmatic subjects however, the bronchial response,
manifested as spasm, is much more severe and sustained.
• A positive family history is uncommon
• serum IgE levels are normal
• there are no associated allergies
• virus-induced inflammation of the respiratory mucosa lowers the
threshold of the subepithelial vagal receptors to irritants.
• the ultimate humoral and cellular mediators of airway obstruction
(e.g., eosinophils) are common to both atopic and non-atopic
variants of asthma.

14. Sputum and BAL
Curschmann’s spiral
• Cork screw shaped twists of condensed mucus
Creola bodies
• Clusters of surface airway epithelial cells
Charcot leyden crystals
• Eosinophil cell and granule membrane
lysophospholipase

15. • Airflow limitation in Asthma is recurrent and are
caused by
 Bronchoconstriction
 IgE dependent mediators from Mast cells
 Airway edema
 Ìnflammation,mucus hypersecretion,mucus
plugs,SM thickness
 Airway hyperresponsiveness
 Airway remodelling

16. Inflammatory cells in Asthma
Eosinophils
Mast cells
Lymphocytes
Monocytes
Neutrophils

17. Eosinophils
• Granulocytes derived from CD 34 cells
• IL-5 development and terminal differentiation
• Exposure to allergen,recruited into airway by chemotactic
signals-chemokine EOTAXIN
• Migration into airway dependant on extravasation of
peripheral blood eosinophils
• adhesion molecules on endothelium (VCAM 1)
On eosinophils (VLA 4)
• Recruitment of eosinophils IL-5,GM-CSF,RANTES
• Upon entry into airway,release mediators granule
proteins,leukotrienes(C₄),PG,cytokines.
• Peripheral blood eosinophilia prominent feature of asthma

19. LYMPHOCYTES
• Prominent source of cytokines
• Increased no of activated T cells(CD₄) in airway
• Th₁ - IL-12,IFN ᵞ
• Th₂ - IL-4,IL-5,IL-9,IL-13
• Th₂ predominant in asthma
• IgE production (IL-4,IL-13)
• Eosinophilia (IL-5)
• Mucus secretion(IL-13)
• Airway hyper responsiveness (IL-13)

22. MAST CELLS
• Leukocytes that are effectors of inflammatory process
• Immature form in peripheral circulation,differentiate upon
localisation to a tissue compartment
• Degranulation → inflammatory mediators
• MC ̞ type- alveoli,bronchi & bronchioles
• Tryptase : ↑ AR to histamine,stimulate fibroblast,↑collagen
• Express high affinity IgE receptor & constitutively bound
• Encountering Allergen,IgE molecules bind with allergen
activates Mast cell
• Immediate release of Histamine,tryptase,followed by LT,PG

23. FATE OF MAST CELLS

24. Macrophage and Dendritic cells
• Phagocytic cells capable of Antigen presenting
• Critical role in clearing of microbes
• Low affinity IgE receptors
• Suppress inflammation by secretion of Th₁
cytokines(IL-12,IL-18,IFN ᵞ )
• Dendritic cells- key antigen presenting cell
• Migrate to regional LN,interact with regulatory
cells to stimulate Th₂ production

25. NEUTROPHILS
• Increased in airways and sputum during acute
exacerbations and in the presence of smoking
• Determinant of lack of response to CS
treatment

26. INFLAMMATORY MEDIATORS
• CHEMOKINES
• CYTOKINES
• LEUKOTRIENES
• PROSTANOIDS
• IgE
• NITRIC OXIDE

27. Chemokines
• Recruitment or chemotaxis of inflammatory
cells
• Additional signalling function
• Attractive target for therapy
• CCR5 inhibitor – currently in use

28. Cytokines involved in pathogenesis of
asthma
IL-4
• cross-linking of immunoglobulines in B
lymphocytes – production of IgE and IgG4
• increases of expression of VCAM-1 and
mucous secretion
• inhibits of activation of Th1 and production of
IFNγ

29. IL-13
• induces production of IgE a IgG4
• activates mast cells
• increases bronchial hyperreactivity and
contractility of smooth muscles, affects the
differentiation of cilia
• induces the production of eotaxin, VCAM-1
• supress production of pro-inflammatory
cytokines

30. IL-5
• produced by mast cells and Th2 lymphocytes,
epithelial cells and eosinophils
• affects the proliferation and the
differentiation of B lymphocytes
• induces expression of IL-2R
• proliferating and differentiating factor for
eosinophils

31. IL-12
• produced by macrophages, dendritic cells and
monocytes
• decreases production of Th2 cytokines and
then production of IgE and IgG1
• decreases number of eosinophils in peripheral
blood and in sputum

32. IL-10
• large immunosupressive and anti-
inflammatory effect
• decreases expression of iNOS, COX2
• decreases release of IL-2, expression of MHC
class II., CD80, CD86 and CD32 on the surface
of APC and then presentation of allergen,
RANTES, IL-5
• correlation with asthma severity

33. IFNγ
• low levels in atopic people
• stimulatory effects on Th1 cells, inhibitory
effects on Th2 cells
• the nebulissation of IFNγ decreases the
number of eosinophils in BAL but this effect is
not significant

34. TGF-β
• remodeling
• induction of expression of Fas receptor on the
surface of epithelial cells, activation of
apoptosis, fagocytosis by macrophages,
exsudation of plasma, fibrosis

35. IgE
• Allergic inflammation prominent role in
asthma
• Mast cell mediators –major role in Asthma
• IgE – Mast cell activation
• As target for therapy
• Omalizumab

36. Leukotrienes
• Arachidonic acid metabolites
• Rapidly synthesised within minutes,following
activation
• LT C4,D4,E4 potent bronchoconstrictors
• Produced by several cell types including
eosinophils,mast cells
• Also increase mucus secretion
• Facilitate plasma leak,generating airway edema

37. PROSTANOIDS
• Arachidonic acid metabolites via COX pathway
• PGD₂,PGF₂,TXA₂ potent bronchoconstrictors
• Produced by eosinophils,mast cells
• PGD₂ predominant prostanoid involved.

39. NITRIC OXIDE
• Role unclear
• Low levels,a bronchodilator & vasodilator
• Higher levels of NO in asthma
• NO react with superoxide anion in inflamed
tissue to produce biologic oxidants
• Level of severity of airway inflammation
• Exhaled NO tool to reflect airway
inflammation

40. AIRWAY EPITHELIUM is central to
pathogenesis of ASTHMA
• Epithelial stimulation to epithelial
shedding,even extensive areas of denudation
• MBP ,EPO & ECP implicated in injury
• Injured & stimulated epithelial cells secrete
GM-CSF,IL-1,IL-8,RANTES.
• Significant denudation of epithelium itself
result in variety of secondary effects

41. • Loss of barrier function permit direct access of
allergens on tissue cells (eg; mast cells)
• Loss of epithelial cells reduces ability to degrade
peptide and kinin mediators and to secrete
EDRF(which maintain dilatation)
• Sensory nerve exposure promote inflammation
and bronchoconstriction
• Provoke proliferation of myofibroblasts,secretion
of extracellular matrix protein(collagen) leading
to thickened BM

43. EXTRACELLULAR MATRIX
• Prominent structural feature in Asthma
• Thickening of lamina reticularis
• Denuded epithelium expose BM to airspace
• Sub BM is enlarged and dense by deposition
of collagen,fibronectin,laminin….
• Epithelial cells and myofibroblasts contribute
to thickening
• GF:TGF B,PDGF,FGF,endothelin

44. FIBROBLASTS AND MYOFIBROBLASTS
• Abnormal mesenchymal cell proliferation & no
of Fibroblasts,Myofibroblasts ↑ed.
• MFB- tissue remodelling by releasing ECM
components elastin,fibronectin,laminin.
• Allergen challenge ↑no of MFB
• Role : contractile
response,mitogenesis,synthetic and secretory.
• Release RANTES

45. SMOOTH MUSCLE CELLS
• Excess accumulation of bronchial smooth muscle cells
prominent feature of airway wall remodeling
• pro-activating signals for converting airway smooth
muscle cells into a proliferative and secretory cell in
asthma are unknown, but may include viruses and IgE
• Another mechanism regulating smooth muscle
proliferation is through production of
metalloproteinase (MMP)-2
• nonspecific BHR is a basic mechanism underlying the
excessive smooth muscle contraction and airway
narrowing

46. NONSPECIFIC BHR
• Major functional abnormality in asthma
• Related to severity of symptoms over long periods
• Response to wide range of stimuli
• Not completely related to bronchial eosinophilic
inflammation
• Easier access of stimulus to epithelial & submucosal
sites enhance BHR
• Loss of epithelial tight junctions α BHR
• Lamina reticularis thickness α BHR
• More prolonged exposure leads to fibronectin,collagen
deposition in the outer airway wall

47. NERVES
• Dysfunction of the airway innervation in asthma contributes
to its pathophysiology.
• β-Adrenergic blockers and cholinergic agonists are known
to induce bronchoconstriction and produce symptoms of
asthma.
• Nonadrenergic noncholinergic (NANC) neural pathways
involving new neuromediators, such as bradykinin,
neurokinin, vasoactive intestinal peptide (VIP), and
substance P.
• These neuromediators produce in vitro and in vivo features
of clinical asthma involving bronchoconstriction,
vasodilation, and inflammation.
• The NANC system has been proposed as an explanation for
bronchial hyperreactivity .
• ↓ VIP secreting neurons

48. BLOOD VESSELS
• Airway wall remodeling in asthma involves a
number of changes including increased
vascularity, vasodilation, and microvascular
leakage.
• number and size of bronchial vessels is
moderately increased.
• neovascularization or angiogenesis is still unclear.
• Vascular endothelial growth factor (VEGF) levels
are variable in asthmatic airways suggesting a low
degree of angiogenesis in patients with controlled
asthma.

49. GLANDS
• Bronchial hypersecretion is the consequence of
hypertrophy and hyperplasia of submucosal glands and
epithelial goblet cells.
• Increased mucus will certainly result in sputum
production and contribute to excessive airway
narrowing.
• The replacement of ciliated cells by goblet cells
contributes to airway remodeling in asthma.
• Impaired clearance of mucus is present during
exacerbations and is a potential important contributor
to fatal asthma.

50. AIRWAY HYPERRESPONSIVENESS
• Increased smooth muscle sensitivity and
contracture
• Dysfunctional neuroregulation
• Increased maximal contraction of bronchial
muscle as consequence of reduction/uncoupling
of opposing forces (elastic recoil)
 Airway wall edema result in functional
detachment of alveolar walls
• Thickening of airway wall due to chronic
inflammation ,result in increased resistance to
airflow

51. AIRWAY REMODELLING
• Inflammation- thickening of subBM
• Mucus hypersecretion (Gland hyperplasia)
• Subepithelial fibrosis
• Airway smooth muscle hypertrophy
• Angiogenesis

52. SUMMARY
• Asthma is characterized by reversible bronchoconstriction
caused by airway hyper-responsiveness to a variety of stimuli.
• Atopic asthma is caused by a TH2 and IgE-mediated
immunologic reaction to environmental allergens and is
characterized by acute (immediate) and late-phase reactions.
The TH2 cytokines IL-4, IL-5, and IL-13 are important
mediators.
• Triggers for non-atopic asthma are less clear but include viral
infections and inhaled air pollutants.
• Eosinophils are key inflammatory cells found in all subtypes of
asthma; eosinophil products such as major basic protein are
responsible for airway damage.
• Airway remodeling (basement membrane thickening and
hypertrophy of bronchial smooth muscle) adds to the
element of obstructive disease.

53. THANK YOU