Case 8: Thomas Gagnon - Asthma

Respiratory Epithelium

Ciliated pseudostratified columnar epithelium

Cells:

• Ciliated Columnar: Apical cilia

• Goblet

• Brush: Apical microvilli, basal nerve endings (chemosensory)

• Small Granule

• Basal: Stem cells

Basement membrane

Lamina propria

Nasal Cavity Epithelium

Respiratory + olfactory epithelia

• Pseudostratified columnar epithelium

• Olfactory neurons

• Supporting cells

• Basal cells

Paranasal Sinuses: Thin respiratory epithelium

• Less goblet cells

Pharynx Epithelium

Naso: Resp epithelium

Oro: Stratified squamous

Laryngo: Loose connective tissue + elastic fibres in lamina propria

Larynx Epithelium

Epiglottis: Stratified squamous epithelium → Resp epithelium

Vestibular Folds: Resp epithelium + seromucous glands + lymphoid nodules

Vocal Folds: Stratified squamous epithelium

Trachea Epithelium

Resp epithelium

Seromucous glands produce mucus

Anterior: C shaped hyaline cartilages

Posterior: Trachealis smooth muscle (for esophagus expansion)

Bronchial Tree Epithelium

Primary Bronchi: Resp epithelium + cartilage rings

• Mucous and serous glands

• Smooth muscles

• Elastic fibres

Other Bronchi: Resp epithelium + hyaline cartilage

• Increase smooth muscles and elastic fibres

Bronchiole Epithelium

Resp epithelium

Connective tissue + smooth muscle

Terminal Bronchiole Epithelium

Ciliated simple columnar or simple cuboidal

• Club Cells: Non-ciliated, contain secretory granules

  • Immune protection

• Brush cells

• Small granule cells

Alveoli Epithelium

Simple squamous epithelium

Smooth muscles, elastic, collagen

Type 1 and 2 pneumocytes

Resp membrane

Alveoli: Alveolar Sacs

Thin elastic and reticular fibres

Alveoli: Interalveolar Septa

Between alveoli

Fibroblasts

ECM: Connective tissues (elastic and reticular fibres)

Alveoli: Resp Membrane

Blood-air barrier

Fused basal lamina (alveolar cell lining) and endothelial cells (capillaries)

Airway Epithelium Physiology

Clean and protect airway

• Secrete mucus

• Mucociliary clearance

Airway Goblet Cells Physiology

Secrete mucins (mucus)

• Trap foreign particles

• Mucociliary clearance

Airway Inflammatory Cell Physiology

Innate host defense

• Release chemokines and cytokines

• Phagocytosis

Airway Smooth Muscle Cell Physiology

Control airflow

• Regulate contraction and relaxation

Secrete ECM proteins

• Contribute to airway remodelling during disease

Factors Influencing Airway Diameter

ANS causing bronchoconstriction and bronchodilation

Smooth muscle hypertrophy

Airway wall thickness (inflammation, edema, mucus)

Lung volume (hyperextension = pull open airways)

Asthma: Description

Resp disease with chronic airway inflammation (hyperactivity)

• Restrict expiration

Allergic and non-allergic

Asthma: Epidemiology

Risk Factors:

• Perinatal/childhood exposures (resp infections, maternal smoking)

• Environmental exposures (smoking, mold, farming)

• NSAIDs

• Genetics

• Obesity

Asthma: Etiology

Bronchial hyper-responsiveness causing chronic inflammation

Asthma: Pathogenesis

1. Immune dysregulation = Persistent inflammatory and structural airway changes

2. Immune cells respond to antigen-induced alarmin molecules to recruit inflammatory cells and cytokines

• Mast cells (histamine), eosinophils

3. Bronchoconstriction + airway obstruction = Low V = Low V/Q

• Hypoxia

Asthma: Investigation

Spirometry:

• Airflow obstruction (flow-volume loop scooping)

• Pre- and post- bronchodilator administration

Peak Expiratory Flow (PEF):

• Max speed when forcibly exhaling air

• Supportive

NO IMAGING

Asthma: Clinical Presentation

Coughing and wheezing

Dyspnea

Chest tightness

Recurring symptoms

• Worse at night

• During exercise

• With allergen exposure

→ GINA severity

Asthma: Treatment/Management

Step-wise approach

• Increase management with severity + previous treatment response

Avoid allergens

Pharmacological

Exacerbations:

• O2 administration

• SABA + IV systemic CS

Asthma Treatment: Pharmacological

Inhaled Corticosteroids (ICS): Inhibit pro-inflammatory gene transcription

Short-Acting Beta-2 Agonist (SABA) and LABA: Bind beta-2 adrenergic receptors = Bronchodilation

• Tachyphylaxis: Rapid tolerance from internalized receptors

Short-Acting Muscarinic Antagonist (SAMA) and LAMA: Prevent acetylcholine binding = Block PNS = Bronchodilation

Ab Therapy: Anti IgE and IL-5

Atopic Triad

3 conditions caused by allergen-triggered IgE mast cell activation

• Commonly manifested together

• Genetic predisposition

Asthma, atopic dermatitis, allergic rhinitis

Atopic Triad: Asthma

Type 1 hypersensitivity

Chronic airway inflammation

1. Initial Sensitization

2. Reexposure

3. Chronic

Asthma: Initial Sensitization

1. APC (dendritic cells) identify and load allergen on MHC II

2. APC present MHC-allergen to helper T-cells for activation

3. Th2 cells release chemical mediators = B-cells produce antigen-specific IgE

4. IgE bind receptors on mast cell and basophils

Asthma: Reexposure

1. Inhaled allergen bind IgE antibody on mast cells in bronchial lumen

2. Activate mast cell to release mediators (histamine, leukotrienes)

• Induce bronchoconstriction and mucus production

3. Antigen binds IgE on mast cells in epithelium = Release more mediators

• Induce bronchoconstriction and inflammation

Asthma: Chronic

Airway remodelling (decreased lumen) from:

• Smooth muscle hypertrophy

• Increased mucus glands

• Epithelial detachment from basement membrane

• Fibrosis

Atopic Triad: Atopic Dermatitis

Eczema: Chronic inflammatory skin disease

Atopic Dermatitis: Etiology

Epidermal barrier dysfunction (tight junctions)

Poor defense against pathogens and water loss

Atopic Dermatitis: Pathogenesis

Type 2 hypersensitivity

1. Filaggrin gene mutation = Increase water loss and pathogen penetration

2. Increase Th2 + cytokines = Increase IgE from B-cells

3. IgE bind receptors (mast cells) = Inflammatory skin response

Atopic Triad: Allergic Rhinitis

Hay Fever: Inflammation of nasal mucosa

Allergic Rhinitis: Etiology

Allergen exposure

Allergic Rhinitis: Pathogenesis

Type 1 hypersensitivity

1. Allergen exposure = Increase APC/dendritic cell presentation to T-cells

2. Increase Th2 cell activation = Increase IgE production from B-cells

3. IgE bind receptors (mast cells, eosinophils, basophils) = Release histamine (inflammation)

Allergies: Description

Abnormal immune response to harmless environmental stimulus

Allergies: Management

Avoid allergens

Anti-inflammatory therapy

• Corticosteroids

• Anti-histamines

Biologic therapy

• Inhibit type 2 cytokine signalling