Pathophysiology and Pharmacology of asthma

What is asthma?

• Recurrent and reversible short-term obstruction of the airways

• Triggered by substances or stimuli that:

  • Are not necessarily noxious

  • Normally do not affect non-asthmatic individuals

What are common triggers of asthma attacks?

• Allergens (in atopic individuals)

• Exercise (especially in cold, dry air)

• Respiratory infections (e.g., viral)

• Smoke, dust, environmental pollutants

What happens in acute asthma at the airway level?

• Acute airway obstruction from smooth muscle contraction

• Mucus hypersecretion and thickening/plugging

• Airway inflammation

What are the common symptoms of acute asthma?

• Dyspnoea (especially on expiration)

• Wheezing

• Coughing

What type of hypersensitivity reaction is asthma?

• Type I (immediate) hypersensitivity reaction

what happens during Sensitisation (first exposure – no symptoms yet)?

• step 1 : exposure to allergen, which is inhaled into the airway

• step 2: Dendritic cells capture the allergen. Allergen is presented to naïve CD4⁺ T cells.

• step 3: Naïve T cells differentiate into TH2 helper T cells.

what are the other steps of sensitisation to asthma?

• step 4: Activated TH2 cells release cytokines:

• IL4, IL13,IL5

What is the role of IL-4 in asthma sensitisation?

• Stimulates IgE production by B cells

• Activates mast cells

What is the role of IL-13 in asthma sensitisation?

• Promotes mucus production from bronchial epithelial and submucosal glands

• Supports IgE class-switching in B cells

• Enhances mast-cell–related responses

What is the role of IL-5 in asthma sensitisation?

• Activates locally recruited eosinophils

• Contributes to airway inflammation

what happens in the second exposure to allgern mechansim?

• Second exposure to allergen causes IgE cross-linking on sensitised mast cells

• Mast cell degranulation releases histamine, leukotrienes, and prostaglandins

• Leads to bronchoconstriction, mucus secretion, airway oedema,

What are the immediate and late-phase reactions in an asthma attack?

• Immediate phase: mainly bronchospasm

• Late phase: inflammatory reaction contributing to airway swelling and hyperreactivity

What happens during the early phase of an asthma attack?

• Bronchoconstriction

• Increased mucus production

• Vasodilation / increased vascular permeability

• Release of inflammatory mediators

What happens during the late phase of an asthma attack?

• Recruitment of leukocytes and T cells by cytokines/chemokines from mast cells and epithelial cells

• Further release of inflammatory mediators

• Contributes to sustained airway inflammation

What happens in the immediate response when an asthmatic is re-exposed to an antigen? (Stepwise)

Step 1: Antigen binds to IgE-IgE receptor complex on mast cells
Step 2: Cross-links IgE receptors → calcium entry into mast cells
Step 3: Mast cells release secretory granules containing histamine
Step 4: Production & release of other mediators (e.g., leukotrienes LTC4, LTD4) → airway smooth muscle contraction
Step 5: Release of chemotaxins (e.g., LTB4) → attract inflammatory cells (eosinophils) to the area

What are the effects of mast cell mediators (histamine and leukotrienes) in the immediate phase of an asthma attack?

• Bronchospasm

• Increased vascular permeability & vasodilation

• Mucus production

• Recruitment of additional mediator-releasing cells from the blood

What happens during the late phase of an asthma attack?

• Arrival of recruited cells: basophils, eosinophils, neutrophils, TH2 lymphocytes

• Release of pro-inflammatory mediators

  • Eosinophils: release major basic protein → epithelial damage & more airway constriction

  • Cytokines: amplify inflammation

What happens during the early phase of allergic asthma?

• Antigen binds to IgE on mast cell receptors

• IgE receptors cross-linked → Ca²⁺ entry into mast cells

• Release of mast cell granules containing:

  • Histamine

  • Leukotrienes (LTC4, LTD4) → smooth muscle contraction / bronchoconstriction

• Release of chemotaxins (e.g., LTB4) → recruit inflammatory cells

What happens during the delayed (late) phase of allergic asthma?

• Recruited cells arrive: eosinophils, basophils, neutrophils, TH2 lymphocytes

• Pro-inflammatory mediators released →

  • Epithelial damage

  • Amplification of inflammation

• Leads to sustained airway obstruction and hyperreactivity

What structural changes occur in chronic asthma (steps 1–3)?

Step 1: Increased mass of smooth muscle → contributes to airway narrowing
Step 2: Accumulation of interstitial fluid (oedema) → thickens airway walls
Step 3: Increased secretion of mucus → further obstructs airflow

What are the functional consequences of airway remodelling in chronic asthma (steps 4–5)?

Step 4: Epithelial damage exposes sensory nerve endings → increases airway sensitivity
Step 5: Airway narrowing by inflammation and bronchoconstriction →

• Increased airway resistance

• Decreased FEV₁ and Peak Expiratory Flow (PEFR)

• Bronchial hyperresponsiveness → airways overreact to triggers

How is asthma diagnosed?

• Demonstration of airflow obstruction:

  • Spirometry

  • Peak-flow test

• Clinical signs: difficulty with exhalation, wheezing on prolonged expiration

• Blood tests: eosinophil count

• Allergy tests: skin prick test, specific IgE blood test

How does parasympathetic innervation regulate the airways?

• Innervates bronchial & vascular smooth muscle, and glands

• Step 1: Acetylcholine (ACh) binds to M3 muscarinic receptors

• Step 2 : The Gq protein activates PLC

• step 3 : PLC converts (PIP₂) into IP₃ and DAG

• Step 4: IP₃ diffuses through the cytoplasm to the endoplasmic reticulum.

• step 5 : IP₃ binds to IP₃ receptors on the ER, causing Ca²⁺ to be released into the cytoplasm.

• step 6 : Stimulation causes:

  • Bronchoconstriction

  • Increased mucus secretion

How does sympathetic innervation regulate the airways? step 1

• step 1 : Adrenergic stimulation: Adrenal medulla releases adrenaline (epinephrine) into the blood.

• Adrenaline binds to β₂-adrenergic receptors on bronchial smooth muscle.

How does sympathetic innervation regulate the airways? step 2-5?

B2 receptor is coupled to Gs protein

Step 2: Gs protein activates adenylyl cyclase
Step 3: Adenylyl cyclase converts ATP → cAMP
Step 4: cAMP activates protein kinase A (PKA)

causes : broncholidation

the second sympathetic innervation: noradrengic

• Step 1: Neuronal noradrenaline is released from sympathetic nerve endings.

  Step 2: Noradrenaline binds to β₂-adrenergic receptors on airway gland cells.

  Step 3: β₂ receptors are Gs-coupled, activating adenylyl cyclase → ↑cAMP → PKA.

  Step 4:this casues decreased mucus production.