Respiratory System: Histology Notes

Respiratory System

Respiration

• Cellular Respiration: Transformation of organic molecules into energy within mitochondria.
• Mechanical Respiration: Release of O2 into the blood and CO2 into the air, facilitating gas exchange in the respiratory system.

Roles of the Respiratory System

• Main Roles:
  • Air transport/conduction
  • Air conditioning: filtration, humidification, and temperature adjustment to body temperature.
  • Gas exchange (respiration)
• Other Roles:
  • Talking and smelling.
  • Endocrine function (hormone production).
  • Immune response to inhaled antigens.

Portions of the Respiratory System

• Main Portions:
  • Air-conducting portion.
  • Respiratory portion.
  • Components ensuring ventilation.
• Anatomical Components: A series of air passages and paired lungs with pleura.

Composition of the Respiratory System

• Air-Conducting Portion:
  • Extrapulmonary: Nasal cavities, sinuses, nasopharynx, oropharynx, larynx, trachea, and paired main bronchi.
  • Intrapulmonary: Bronchial tree (bronchi, bronchioles, terminal bronchioles).
• Respiratory Portion: Respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli.
• Ventilation System: Rib cage, intercostal muscles, diaphragm, elastic connective tissue of the lung.
  *Accompanied by blood vessels, lymphatic vessels, capillaries

Histological Elements for Air Transport and Conditioning

• Hyaline Cartilage Framework: Maintains open airways.
• Mucosa: Rich in blood vessels for warming air; ciliated cells for transport and cleaning; mucus and serous secretions for protection and moistening.
• Elastic Fibers: Longitudinal placement ensures airway dilation.
• Smooth Muscles: Spiral arrangement narrows airways.

Components of the Respiratory and Conducting Zone

• Epithelium
• Goblet cells
• Hyaline cartilage
• Smooth muscle
• Elastic fibers

Functions of the Air-Conducting Portion

• Provides passage for inhaled and exhaled air.
• Located outside (extrapulmonary) and inside (intrapulmonary) the lung.
• Site of air conditioning: warming, moistening, and particle removal.

Functions of the Respiratory Portion

• Involved in gas exchange between air and blood.

Functions of the Ventilation System

• Ensures inflow (inspiration) and outflow (expiration) of air.

Nasal Cavities and Paranasal Sinuses

• Functions:
  • Extensive surface area for warming and moistening air.
  • Filtering dust particles.
  • Olfactory mucosa in the roof of each nasal cavity and part of the superior concha.

Organization of Nasal Cavities

• Entrance: Nostril or naris.
• Separated by bony and cartilaginous septum.
• Consists of:
  • Vestibule.
  • Respiratory portion (regio respiratorica).
  • Olfactory area (regio olfactoria).

Communication of Nasal Cavities

• Anteriorly: Exterior environment through nostrils.
• Air-containing cavities: Maxillary, frontal, ethmoidal, and sphenoid sinuses.
• Posteriorly: Pharynx (nasopharynx and oropharynx).
• Middle ear: Opening of the auditory (Eustachian) tubes.
• Nasolacrimal duct: Draining tears from the eye.

Lymphoid Tissue in Nasal Cavities

• Abundant mucosa-associated lymphoid tissue (MALT) present beneath the nasopharyngeal epithelium - Waldeyer's ring.
• Nasopharyngeal tonsils (adenoids): At the posterior and upper regions of the nasopharynx.

Nasal Cavity Components

• Nostril:
  • Lined by keratinized squamous stratified epithelium of the skin.
  • Contains sebaceous and sweat glands.
  • Short, thick hairs for removing larger foreign bodies.
• Vestibule:
  • Non-keratinized squamous epithelium.
  • Vibrissae to entrap particles and sebaceous glands.
  • Epithelium becomes thinner, transitioning to pseudostratified epithelium in the posterior part.

Respiratory Portion of Nasal Cavities

• Epithelium:
  • Pseudostratified columnar epithelium with ciliated cells, goblet cells, brush cells, basal cells, and Kulchitsky cells.
  • Endoepithelial glands.
• Lamina Propria:
  • Connective tissue, seromucous glands (glandulae nasales with mucous and mixed acini).
  • Capillary loops and a rich superficial venous plexus.

Lamina Propria Function and Composition

• Mucous and Serous Secretion: Major role in air conditioning.
  • Serous secretion: Moistens the mucosal surface and humidifies the air.
  • Mucous secretion: Goblet cells form a mucus layer that retains dust particles.
• Capillaries: Parallel arrangement warms incoming air.
• Immune Response: Macrophages, neutrophiles, eosinophiles (increased in allergies), lymphocytes, plasma cells (secreting IgA, IgG, IgE).

Clinical Correlations of Nasal Cavities

• Highly vascular nature accounts for:
  • Common bleeding (epistaxis) after trauma.
  • Acute inflammation (rhinitis) during allergic reactions or viral infections.
  • Engorged and leaky vessels, leading to swelling and restricted air passage.
• Lamina propria distension with fluid, resulting in marked swelling of the mucous membrane making breathing difficult

Structural Details of Respiratory Portion

• Lamina propria is continuous with:
  • Periosteum of bone or perichondrium of cartilage, forming the wall of the nasal cavities.
• Lateral wall contains:
  • Three curved plates of bone – conchae (superior, middle, inferior turbinate bones).
• Functions:
  • Increases surface area for warming the air.
  • Causes airflow turbulence, enhancing contact between air and mucus blanket.
  • Traps particulates, transported posteriorly by ciliary action to the nasopharynx, where they are swallowed.

Olfactory Area of Nasal Cavities

• Epithelium:
  • Olfactory epithelium: Pseudostratified epithelium with basal cells, olfactory receptor cells, supporting cells, and brush cells.
• Lamina Propria:
  • Continuous with the periosteum.
  • Connective tissue rich in blood and lymphatic vessels.
  • Olfactory serous glands (glands of Bowman).
  • Unmyelinated olfactory nerve bundles.

Olfactory Mucosa

• Olfactory Epithelium:
  • Basal cells: Mitotically active stem cells, producing new olfactory and supporting cells.
  • Supporting cells: Columnar cells with microvilli, lipofuscin granules, and numerous organelles.
    • Role: Provide mechanical and metabolic support to olfactory cells; secrete odorant-binding protein (OBP).

Olfactory Receptor Cells

• Bipolar Neurons:
  • Apical domain: Single dendritic process projecting above the epithelial surface with non-motile cilia.
  • Basal domain: Unmyelinated axon passing through the basement membrane, entering the lamina propria.
  • Lifespan: About 1 month; readily replaced if injured.
    *unmyelinated axon
  • Replaced during postnatal life

Olfactory Nerve Filaments

• Composed of small unmyelinated nerve bundles surrounded by glial-like cells.
• Cross the cribriform plate of the ethmoid bone.
• Enter the olfactory bulb and establish synaptic connections with dendrites of mitral cells (neurons).
• Axons form the olfactory tract

Clinical Correlation: Anosmia

• Loss of Smell:
  • Permanent: Traumatic head injury severing olfactory axons.
  • Temporary: Viral infections, e.g., SARS-CO-V-2 accumulating in sustentacular cells.

Lamina Propria (Olfactory Mucosa)

• Connective tissue containing olfactory serous glands (glands of Bowman).
  • Branched tubulo-alveolar serous glands with short excretory ducts.
  • Lipofuscin granules prevalent in gland cells.
    Secretory Product: Serous Fluid
    *Odoriferous substances are dissolved
  • Trap and solvent for odoriferous substances *Constant flow for washing up the remnants of detected odoriferous substances
    • Contains odorant-binding protein (OBP) – secreted by the supporting cells - with high binding affinity for a large number of odorant molecules
    • OBP carries odorants to receptors present on the surface of the modified cilia and removes them after they have been sensed
      • Rich in proteins and protective substances such as lysozyme and IgA secreted by plasma cells
        *Odorant molecules stimulate olfactory receptors, activate adenylyl cyclase, and initiate the cAMP cascade, leading to depolarization and action potential generation.

Paranasal Sinuses

• Air-filled spaces in the bones of the nasal cavity walls.
• Extensions of the respiratory region of the nasal cavities, lined by respiratory epithelium.
• Communicate with the nasal cavities via narrow openings.
  *Increase surface area for air filtration, warming, moistening and modulation of sounds

Pharynx

• Connects the nasal and oral cavities to the larynx and esophagus.
• Divided into the nasopharynx and oropharynx.
• Auditory (Eustachian) tubes connect the nasopharynx to each middle ear. *Concentration of lymphatic nodule - called the pharyngeal tonsil.
  • Passageway for air and food and the resonating chamber for speech

Larynx

• Passageway for air between the oropharynx and trachea.
• Formed by irregularly shaped plates of hyaline and elastic cartilage.
• Lined by stratified squamous (vocal cords) and ciliated pseudostratified columnar epithelium.
  *Conduit for air and organ for producing sounds

Trachea

• Major segment of the conducting region.
• Continuation of the larynx, branching into primary bronchi.
• Tube-like structure with:
  • Mucosa: Epithelium and lamina propria.
  • Submucosa.
  • Fibroelastic-cartilaginous layer (C-shaped cartilages).
  • Adventitia.

Trachea Epithelial Lining

• Respiratory epithelium: Pseudostratified columnar ciliated epithelium.
  • Columnar ciliated cells.
  • Brush cells.
  • Goblet cells.
  • Small granule cells (Kulchitsky cells).
  • Basal cells.

Respiratory Epithelium Cell Types

• Columnar Ciliated Cells:
  • Predominant, with eosinophilic cytoplasm and oval nuclei.
  • 250-300 cilia functioning as a mucociliary escalator.
• Brush Cells:
  • Columnar cells with blunt microvilli.
  • Involved in absorption and serous secretion.
  • Synaptic contact with afferent nerve endings; function as receptor cells.

Respiratory Epithelium Additional Cell Types

• Goblet Cells:
  • Interspersed between ciliated cells, secreting mucus.
  • Increase in number during chronic respiratory diseases.
• Basal Cells:
  • Rest on the basal lamina, undifferentiated stem cells.

Small Granule Cells (Kulchitsky cells)

• Respiratory representatives of enteroendocrine cells.
• Secrete peptide hormones (cathecolamine, serotonin, calcitonin, GRP).
• Present in groups, forming neuroepithelial bodies sensitive to O_2.
• Function in reflexes regulating airway or vascular caliber.
• Origin of bronchial carcinoid tumors.

Trachea Layers: Basement Membrane and Lamina Propria

• Basement Membrane:
  • Thick (25-40 µm).
  • Increases in thickness in smokers and those with chronic coughing.
• Lamina Propria:
  • Loose connective tissue with numerous cells (fibroblasts, plasma cells, mast cells, eosinophils, lymphocytes).
  • Lymphatic tissue (BALT).
  • Collagen and elastic fibers, concentrated in an elastic membrane.

Trachea Layers: Submucosa and Fibroelastic-Cartilaginous Layer

• Submucosa:
  • Slightly denser connective tissue, blood and lymphatic vessels, lymphatic tissue.
  • Tracheal glands with mixed acini.
• Fibroelastic-Cartilaginous Layer:
  • 15-20 C-shaped hyaline cartilages.
  • Trachealis muscle (smooth muscle fibers) at the posterior side.
    Adventitia: Loose connective tissue binding the trachea to adjacent structures, containing blood vessels, nerves, and lymphatics.

Bronchi: General Structure

• Two segments: extrapulmonary and intrapulmonary
• Arise from the trachea and branch into main bronchi, then lobar bronchi.
• Secondary divisions divide each lung into lobes (2 in left and 3 in right) Bronchopulmonary Segments
  • Gross anatomic units of the lung that can be removed surgically
  • 8 in the left lung and 10 in the right lung
    The hilum - the region where the primary bronchus, pulmonary artery, pulmonary vein, nerves, and lymphatics enter and leave the lung.
• Each with their own blood supply and connective tissue septa, are convenient subunits that facilitate surgical resection.

Subdivisions of Bronchi

• The primary or main bronchi
• Initially have the same histologic structure as the trachea
• Cartilage rings are replaced by irregular cartilage plates
  *subdivide into lobar bronchi  segmental bronchi  primary bronchioles terminal bronchioles respiratory bronchioles  2-11 alveolar ducts  5-6 alveolar sacs

Organization of Pulmonary Structures

• Pulmonary Lobule: Supplied by a bronchiole and delimited by fine septa.
• Pulmonary Acinus: Supplied by a terminal bronchiole; includes respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli.
• Respiratory Bronchiolar Unit: Smallest functional unit, consisting of a single respiratory bronchiole and its supplied alveoli.

Smooth and elastic muscle

• Smooth muscle fibers are oriented concentrically, in a spiral fashion
• Elastic fibers are oriented longitudinally
• Pores of Kohn connect adjacent alveoli

Intrapulmonary Bronchus Structure (>1 mm Diameter)

• 5 layers
• Mucosa:
  • Respiratory epithelium and lamina propria (reduced amount).
• Muscle Layer:
  • Smooth muscle bundles in a circular + spiral arrangement (Reisseissen muscle).
• Submucosa:
  • Loose connective tissue, mixed glands, adipose tissue.
• Cartilage Layer:
  • Irregularly shaped cartilage plates, smaller as diameter decreases.
• Adventitia:
  • Moderately dense connective tissue, continuous with adjacent structures.

Bronchioles: Structure (<1 mm Diameter)

• Pseudostratified columnar ciliated epithelium transitioning to simple columnar ciliated epithelium.
• Thin lamina propria with elastic fibers.
• Well-developed layer of muscle bundles with circular or spiral arrangement.
• Goblet cells present in largest bronchioles, absent in terminal bronchioles (except in smokers).
• No glands, cartilage islets/plates, or adventitia.

Terminal Bronchioles Composition

• Last part of the conducting portion, branching into respiratory bronchioles.
• Wall Structure:
  • Simple columnar changing into simple cuboidal epithelium with ciliated cells, neuroendocrine cells, and cells with microvilli (neuropithelial bodies), and Clara cells.

Clara Cells

• Nonciliated cells with a dome-shaped apical surface.
• Characteristics of protein-secreting cells (well-developed rER, Golgi apparatus, sER).
• Secrete a lipoprotein (surfactant) to prevent luminal adhesion, and Clara cell secretory protein (CC16).

Clinical Correlation (Clara Cells)

• Chronic lung diseases (COPD and asthma) associated with changes in CC16 abundance.
• CC16 used as a pulmonary marker in broncho-alveolar lavage fluid and serum.
• Secretion of CC16 decreases during lung injury, serum levels may increase due to leakage across the air–blood barrier.

Terminal Bronchioles Composition

• Lamina Propria: Thin layer with few elastic fibers.
• Muscle Layer: Circumferential layer of smooth muscle fibers with spiral arrangement.

Respiratory Bronchioles

• Transitional zone between air conduction and gas exchange.
• Diameter <0.5 mm.
• Discontinuous wall with scattered, thin-walled alveoli.
  Lining
  *Ciliated non ciliated simple cuboidal epithelium
  Collagen+ reticular fibers preventing too large dilation
• Smooth muscle layer

Respiratory Bronchioles Continued

• Epithelium:
  • Nonciliated, Clara cells (increased distally).
  • Isolated ciliated cells (decreased distally).
  • Brush cells.
  • Isolated dense-core granule cells (neuroendocrine cells).

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Alveolar Ducts

• Elongated airways, dilated structures
• *2-11 alveolar ducts
  • *Tiny end ducts
• With almost walls, only alveoli at openings of alveoli.
• Continuous Wall:
  • Simple squamous epithelium (alveolar epithelium).
    Fine network: collagen, reticular elastic fibers
    Few smooth muscle fibers

Alveolar Sacs

• Spaces surrounded by clusters of alveoli.
• Discontinuous wall due to alveoli openings.

Alveoli

• Polygonal respiratory chambers (0.2-0.5 mm diameter).
• Sponge-like arrangement of gas-filled spaces.
• Site of gas exchange, increasing surface area.
• Lined by alveolar epithelium.
• Separated by a connective tissue layer containing blood capillaries (interalveolar septa or septal wall).

Interalveolar Septum

• Capillaries (continuous endothelial lining).
• Collagen, reticular, and elastic fibers.
  *Elastic fibers allow alveoli to stretch and recoil.
• Septal cells: Fibroblasts, alveolar macrophages, pericytes, lymphocytes, plasma cells, mastocytes.

Alveolar Macrophage Functionality

• Large cells, abundant lysosomes (dust cells).
• Free cells migrating over the alveolar surface, defending the alveolar wall.
• Leave airways via lymphatic passages, become bound to mucus, or remain in septa (smokers).
  Collateral Air Circulation
• Monitor inhaled substances (dust and bacteria)
• Allows air to pass between alveoli in case of small bronchiole obstruction.

Epithelial Cell Types of Alveoli

• Type I pneumocyte (type I alveolar cell).
• Type II pneumocyte (type II alveolar cell).
• Brush cells.

Alveoli: Type I Alveolar Cells

• Comprise 40% of cell population, but line 95% of alveolar surface.
• Flattened squamous cells (4-6 μm), few organelles.
• Connected through zonula occludens (tight junctions).
  Role: Intervening in passive gases exchange

Alveoli: Type II Alveolar Cells

• Secretory cells, 60% of cell population, line 5-10% of alveolar surface.
• Larger cuboidal cells (8-12 μm), rich in organelles.
• Apical pole filled with lamellar bodies (pulmonary surfactant).
• Role: Secrete surfactant, progenitor cells for type I cells.
• Differentiate between 24 and 34 weeks
• Surfactant synthesis after 35 weeks of gestation

Pulmonary Surfactant

• Surface-active lipoprotein complex (phospholipid and protein mixture).
• Coats all alveoli, reducing surface tension, and ensuring all alveoli in the lungs expand at the same rate
• Nutritive function
• participates in clearance of foreign materials and help migration of macrophages

Air–Blood Barrier

• The alveolar septum where gas exchange occurs.
• Presence or absence of connective tissue
  • Thin portion (most gas exchange) and thick portion
    Thin Portion
    *Surfactant layer
    *Type I pneumocyte
    *Basal lamina
    Thick Portion
    *Connective tissue with cells and fibers
    *Basal lamina of endothelial cells
    *Capillary endothelial cells

Lungs: General Structure

• Air conducting segment.
• Gas exchange segment.
• Stroma: Loose connective tissue, alveolar macrophages.
• Nerves, blood vessels.

Pleura

• Two-layered membranous structure with a thin cavity in-between.
• Parietal pleura: Adipose tissue with fibrous connective tissue.
• Visceral pleura: 5 layers.
  Simple Squamous epitheliun
  Thin Loose connective tissue layer
  Irregular layer of elastic fibers
  Smooth muscles+ vessels+ nerves
  Elastic fibers that are continuous with those in the interalveolar septa

Clinical Correlations

• Surfactant Deficiency:
  • In premature infants, causing neonatal respiratory distress syndrome (RDS) associated with hyaline membrane disease (HMD).
  • Administration of exogenous surfactant and cortisol to mothers reduces mortality.
    *Emphisema:
    Thin-walled air spaces
    destruction of the elastic wall -> excess lysis of elastin
• Pneumonia:
  filled with exudate containing white blood cells
  red hepatization stage of the pneumonia
• Cystic Fibrosis:
  Mutation of a gene -> abnormally viscid mucus
  Abnormal epithelial transport of Cl ions
  leading to thickening of the bronchiole wall and to other degenerative changes in the alveoli

Blood Supply

• Pulmonary Circulation:
  • From the pulmonary artery, carrying deoxygenated blood to alveolar capillaries.
    Carries deoxygenated blood to the alveolar system
  • Oxygenated in alveolar septum
    *Blood via the pulmonary veins
• Bronchial Circulation:
  • From bronchial arteries, supplying lung tissue except alveoli.
  • Carries oxygenated blood, anastomosing with pulmonary circulation.

Nerves

• Components of sympathetic and parasympathetic divisions.
• Control dimensions of air passages and glandular secretion.