Asthma is associated with a
specific chronic inflammation of
the mucosa of the lower
• 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
• In fatal asthma there will be thickened and
edematous wall along with occlusion of
lumen by mucus plug
• 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
• There is inflammation in the respiratory
mucosa from the trachea to terminal
bronchioles, but with a predominance in
• The specific pattern of airway inflammation
is assosciated with airway
• 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
MAST CELLS: Are activated by allergens through an
• 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
Macrophages and dendritic cells:
• Macrophages initiate a type of inflammatory
response via the release of certain
• Dendritic cells are the major antigen
• Migrate to regional lymphnodes,interact with
regulatory cells to stimulate TH₂ production.
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.
• Prominent source of cytokines
• Increased no of activated T cells(CD₄) in
• 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)
• Recruitment or chemotaxis of inflammatory cells
• Additional signalling function
• Attractive target for therapy
• Multiple cytokines regulate chronic inflammation of
• The TH2 cytokines IL-4,IL-5 and IL-13 mediate allergic
• TNF-α and IL-1β, amplify the inflammatory response
• Thymic stromal lymphopoietin causes release of
chemokines that attract TH2 cells.
• Arachidonic acid metabolites
• Rapidly synthesised within minutes,following
• LT C4,D4,E4 potent bronchoconstrictors
• Produced by several cell types including
• Also increase mucus secretion
• Facilitate plasma leak,generating airway
• Arachidonic acid metabolites via COX pathway
• PGD₂,PGF₂,TXA₂ potent bronchoconstrictors
• Produced by eosinophils,mast cells
• PGD₂ predominant prostanoid involved.
• 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
AIRWAY EPITHELIUM is central to
pathogenesis of ASTHMA
• Epithelial stimulation to epithelial
shedding,even extensive areas of
• Injured & stimulated epithelial cells secrete
• Significant denudation of epithelium itself
result in variety of secondary effects
• 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
• 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
• GF:TGF B,PDGF,FGF,endothelin
• Abnormal mesenchymal cell proliferation &
no of Fibroblasts,Myofibroblasts ↑ed.
• MFB- tissue remodelling by releasing ECM
• Allergen challenge ↑no of MFB
• Role : contractile
• Release RANTES
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
• Another mechanism regulating smooth muscle
proliferation is through production of
• Nonspecific BHR is a basic mechanism underlying
the excessive smooth muscle contraction and
• 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
• Nonadrenergic noncholinergic (NANC) neural pathways
involving new neuromediators, such as bradykinin,
neurokinin, vasoactive intestinal peptide (VIP), and
• 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 .
• 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
• 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
• 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
• 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.
• 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