- Asthma is associated with chronic inflammation of the lower airways, characterized by infiltration of eosinophils, mast cells, and T lymphocytes. There is thickening of the basement membrane and mucus plug formation. - The specific pattern of airway inflammation involves mast cells, macrophages, dendritic cells, eosinophils, neutrophils, and T lymphocytes and their release of inflammatory mediators like chemokines, cytokines, leukotrienes, and prostanoids. - Chronic inflammation leads to structural changes in the airways called airway remodeling, involving thickening of the subepithelial basement membrane, smooth muscle hypertrophy, goblet cell hyperplasia, subepithelial fibrosis,

1. PATHOGENESIS OF
ASTHMA
By,
TEJA NAVEEN.B

2. Asthma is associated with a
specific chronic inflammation of
the mucosa of the lower
airways.

3. PATHOLOGY
• The airway mucosa is infiltrated with
activated eosinophils and T lymphocytes,
and there is activation of mucosal mast cells.
• A characteristic finding is thickening of the
basement membrane due to subepithelial
collagen deposition.
• In fatal asthma there will be thickened and
edematous wall along with occlusion of
lumen by mucus plug

4. • Mucous plug is formed by glycoproteins
secreted from goblet cells and plasma
proteins from leaky bronchial vessels.
• There is also vasodilation and angiogenesis.
• Pathologic changes are found in all
airways,but do not extend to lung
parenchyma.

6. INFLAMMATION
• There is inflammation in the respiratory
mucosa from the trachea to terminal
bronchioles, but with a predominance in
bronchi.
• The specific pattern of airway inflammation
is assosciated with airway
hyperresponsiveness(AHR)
• This physiological abnormality is assosciated
with variable airflow obstruction.
• Many inflammatory cells are know to be
involved in asthma with no key cell that is
predominant.

7. INFLAMMATORY CELLS
• MAST CELLS
• MACROPHAGES AND DENDRITIC CELLS
• EOSINOPHILS
• NEUTROPHILS
• T-LYMPHOCYTES

8. MAST CELLS: Are activated by allergens through an
IgE-dependent mechanism.
• Mast cells release several bronchoconstrictor
mediators like histamine,prostaglandin D2,and
cysteinyl leukotrienses, but also several cytokines,
chemokines,growth factors and neurotrophins.
NEUTROPHILS:Increased in airways and sputum during
acute exacerbations and in the presence of smoking
• Determinant of lack of response to CS treatment

9. Macrophages and dendritic cells:
• Macrophages initiate a type of inflammatory
response via the release of certain
cytokines.
• Dendritic cells are the major antigen
presenting cells.
• Migrate to regional lymphnodes,interact with
regulatory cells to stimulate TH₂ production.

10. Eosinophils: These infiltration is a characteristic feature
of asthmatic airways.
• These are linked to the development of AHR
through the release of basic protiens and oxygen
derived free radicals.

11. T-LYMPHOCYTES
• Prominent source of cytokines
• Increased no of activated T cells(CD₄) in
airway
• TH₁ - IL-12,IFN-ɣ
• 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)

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

13. CHEMOKINES:
• Recruitment or chemotaxis of inflammatory cells
• Additional signalling function
• Attractive target for therapy
CYTOKINES:
• Multiple cytokines regulate chronic inflammation of
asthma
• The TH2 cytokines IL-4,IL-5 and IL-13 mediate allergic
reaction
• TNF-α and IL-1β, amplify the inflammatory response
• Thymic stromal lymphopoietin causes release of
chemokines that attract TH2 cells.

14. 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

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

17. 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

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

19. • 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
basement membrane

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

22. 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

23. 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

24. 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 .

25. 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.

26. 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.

27. 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

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

29. THANK YOU