Respiratory Tract Anatomy, Function, and Blood-Brain Barrier

Posted on Feb 12, 2025 in Biotechnology

Respiratory Tract: Composition and Function

The respiratory tract includes:

Nose (nasal cavity) -> Pharynx (nasopharynx, oropharynx, laryngopharynx) -> Larynx -> Trachea -> Bronchi (primary, secondary (lobar), tertiary (segmental) -> Bronchioles -> Terminal bronchioles -> Respiratory bronchioles -> Alveolar ducts -> Alveoli

Trachea

  • Tough but flexible “windpipe”, anterior to esophagus
  • Attached to cricoid cartilage (at about C6 vertebral level) & ends within mediastinum by branching into left & right primary bronchi (at T5 vertebral level)
  • End of trachea known as Carina
  • Lined with respiratory epithelium
  • “C”-shaped pieces of hyaline cartilage protecting airway while allowing for swallowing
  • Trachealis muscle (smooth muscle) runs across posterior wall of trachea connecting ends of tracheal cartilage
  • Membranous tube of dense regular connective tissue and smooth muscle; supported by 15-20 hyaline cartilage C-shaped rings (protects & maintains open passageway for air). Posterior surface is devoid of cartilage & contains elastic ligamentous membrane and bundles of smooth muscle called the trachealis.
  • Contracts during coughing—this causes air to move more rapidly through trachea, which helps expel mucus & foreign objects.
  • Inner lining: pseudostratified ciliated columnar epithelium with goblet cells. Mucus traps debris, cilia push it superiorly toward larynx and pharynx.

Divides to form:

Left and right primary bronchi (each extends to a lung)

Carina: cartilage at bifurcation (forms ridge). Membrane of carina especially sensitive to irritation and inhaled objects initiate the cough reflex

Bronchi

  • Trachea splits into a left & right primary bronchus which enters into the hilus of each lung
  • Within the lung, the primary bronchi branch into secondary (lobar) bronchi (3 in right lung/2 in left lung)
  • Secondary bronchi then branch into 10 tertiary (segmental) bronchi
  • Tertiary bronchi then continue to branch into smaller & smaller bronchi & then into very narrow bronchioles

This branching pattern creates the “bronchial tree”

Changes in Airway

As you go further down into the bronchial tree of each lung, changes in the airway occur:

  • increased number of airways (1 primary; 2 or 3 secondary; 10 tertiary bronchi; 6000 terminal bronchioles; millions of alveolar ducts)
  • decreased diameter of each airway
  • decreased amount of cartilage in the airways (no cartilage at all by terminal bronchioles)
  • increased amount of smooth muscle (relative to diameter)
  • lining epithelium changes from PSCC, a simple squamous epithelium (in alveoli)

Cartilage: holds tube system open; smooth muscle controls tube diameter

ex: during exercise, diameter increases, decreases resistance to airflow, increases volume of air moved during asthma attack, diameter decreases, increases resistance to airflow, decreases volume of air flow

  • As tubes become smaller, amount of cartilage decreases, amount of smooth muscle increases——ex: terminal bronchioles have no cartilage & only have smooth muscle.

Lungs

Located within the thoracic cavity, surrounded by the double-layered pleural membrane: parietal pleura – lines cavity wall visceral pleura – covers the lungs

  • Each lung has a primary bronchus entering at the hilus
  • Each lobe of a lung has a secondary (a.k.a. lobar) bronchus
  • Lobes are functionally divided into bronchopulmonary segments & each segment has a tertiary (segmental) bronchus
  • Segments are functionally divided into many lobules & each lobule receives a terminal bronchiole

Relationship of Airways & Pulmonary Vessels

  • As airways branch within lungs, they are accompanied by branches of the pulmonary artery (carrying de-oxygenated blood into the lungs), & branches of the pulmonary veins (carrying oxygenated blood out of the lungs)
  • As the alveolar ducts expand to form alveoli, pulmonary arterioles will branch to form a network of pulmonary capillaries, surrounding the alveoli


The Respiratory Membrane

  • Three types of cells in membrane.
    1. Type I pneumocytes. Thin squamous epithelial cells, form 90% of surface of alveolus. Gas exchange.
    2. Type II pneumocytes. Round to cube-shaped secretory cells. Produce surfactant (makes it easier for alveoli to expand during inspiration).
    3. Dust cells (phagocytes)
  • Layers of the respiratory membrane
    1. Thin layer of fluid lining the alveolus
    2. Alveolar epithelium (simple squamous epithelium
    3. Basement membrane of the alveolar epithelium
    4. Thin interstitial space
    5. Basement membrane of the capillary endothelium
    6. Capillary endothelium composed of simple squamous epithelium
  • Tissue surrounding alveoli contains elastic fibers that contribute to recoil.

Alveoli

  • Alveoli are expanded chambers of epithelial tissue that are the exchange surfaces of the lungs
  • There are about 150 million alveoli in each lung
  • Multiple alveoli usually share a common alveolar duct, creating “alveolar sacs”

There are three types of cells found within alveoli:

  • Alveolar Squamous epithelial (aka “type I”) cells
    1. primary cells making up the wall of the alveoli
  • Septal (aka “type II”) cells
    1. secrete “surfactant” to reduce surface tension which prevents alveoli from sticking together & allows for easier gas exchange
  • Alveolar macrophages (aka “dust cells”)
  1. phagocytic cells that remove dust, debris & pathogens


Physiology of Breathing

Gas “exchange” occurs across the Respiratory membrane – the fused membranes of the alveolar epithelium & the pulmonary capillary endothelium

Barometric air pressure is always assigned a value of zero

Inspiration & Expiration

Inspiration: diaphragm, external intercostals, pectoralis minor, scalenes

  • Diaphragm: dome-shaped with base of dome attached to inner circumference of inferior thoracic cage. Central tendon: top of dome which is a flat sheet of connective tissue.
    1. Quiet inspiration: accounts for 2/3 of increase in size of thoracic volume. Inferior movement of central tendon and flattening of dome. Abdominal muscles relax
    2. Other muscles: elevate ribs and costal cartilages allow lateral rib movement
  • Expiration: muscles that depress the ribs and sternum: such as the abdominal muscles and internal intercostals.
  • Quiet expiration: relaxation of diaphragm and external intercostals with contraction of abdominal muscles
  • Labored breathing: all inspiratory muscles are active and contract more forcefully. Expiration is rapid

Blood-Brain Barrier (BBB)

  • Structural & functional barrier which impedes & regulates the influx of most compounds from blood to brain
  • Formed by brain microvascular endothelial cells (BMEC), astrocyte end feet & pericytes
  • Essential for normal function of CNS (central nervous system)
  • Regulates passage of molecules in and out of the brain to maintain neural environment
  • Responsible for metabolic activities such as the metabolism of L-dopa to regulate its concentration in the brain.
  • It´s a semi-permeable capillary membrane; it allows some materials to cross, but prevents others from crossing. In most parts of the body the capillaries, are lined with endothelial cells. The endothelial tissue has small spaces between each individual cell so substances can move readily between the inside & the outside of the vessel. However, in the brain, the endothelial cells fit tightly together & substances cannot pass out of the bloodstream. (Some molecules, such as glucose, are transported out of the blood by special methods such as active transport.)
  • Extensive capillaries & sinuses
  • Tight junctions: limit permeability
  • Astrocyte foot processes: secrete paracrines
  • Protects brain: hormones & circulating chemicals
  • Many glucose transporters


Functions & Properties of the BBB

  • Protects the brain from “foreign substances” in the blood that may injure the brain
  • Protects the brain from hormones & neurotransmitters in the rest of the body
  • Maintains a constant environment for the brain
  • Structure of the Blood Brain Barrier

Differences between BMEC & normal endothelial cells

  • Structural differences:
    • Absence of fenestrations
    • More extensive tight junctions (TJ)
  • Functional differences
    • Impermeable to most substances
    • Sparse pinocytic vesicular transport
    • Increased expression of transport & carrier proteins: receptor mediated junctions
    • No gap junctions, only tight junctions
    • Limited paracellular & transcellular transport

Integrity of BBB: tight junctions, adherens junctions, pericytes & astrocyte end feet

Tight junctions between BMEC

  • Appear at sites of apparent fusion between outer leaflets of plasma membrane of endothelial cells
  • Continuous
  • Anastomosing
  • Intramembranous strands or fibrils on P face with complementary groove on E face
  • Protein components
    1. Claudin
    2. Occludin
    3. Junction Adhesion Molecules
    4. Accessory proteins

Claudin

  • 22 kDa phosphoprotein
  • 4 Transmembrane domains
  • Localized in TJ strands

Occludin

  • 65 kDa phosphoprotein
  • 1º structure very different from claudin
  • Regulatory proteins: alters paracellular permeability


Barrier Function of Occludin & Claudin

  • Assemble into heteropolymers & form intramembranous strands which contain channels allowing selective diffusion of ions & hydrophilic molecules.
  • Breakdown of BBB in tissue surrounding brain tumors occurs with concomitant loss of 55kDa occluding expression

Junctional Adhesion Molecules

  • 40 kDa
  • Integral membrane protein, single transmembrane region
  • Belongs to immunoglobulin superfamily
  • Localizes at tight junctions
  • Involved in cell-to-cell adhesion & monocyte transmigration through BBB
  • Regulates paracellular permeability & leukocyte migration
  • Also found on circulating leukocytes, platelets & lymphoid organs.

Barrier function of JAM

  • Homotypic binding between JAM molecules on adjacent endothelial cells acts as a barrier for circulating leukocytes
  • Heterotypic binding of endothelial JAM to leukocyte JAM might guide transmigration of leukocytes across interendothelial junctions
  • So factors that decrease leukocyte migration must either strengthen homotypic interactions or weaken heterotypic interactions.

Cytoplasmatic accessory proteins

  • ZO-1, ZO-2, ZO-3, cingulin, etc.)
    1. These link membrane proteins to actin
    2. Maintenance of structural and functional integrity of endothelium
    3. Crosslink transmembrane proteins
  • Membrane associated guanylate kinase-like proteins (MAGUKS)
    1. Subunits function as protein binding molecules
    2. Role in organization the plasma membrane

Adherence junction

  • Complex between membrane protein cadherin & intermediary proteins called catenins
  • Cadherin-catenin complex joins to actin cytoskeleton
  • Form adhesive contacts between cells
  • Assemble via homophilic interactions between extracellular domains of calcium ion dependent cadherins on surface of adjacent cells


Pericytes

  • Cells of microvessels including capillaries, venules, & arterioles that wrap around endothelial cells
  • Provide structural support & vasodynamic capacity to microvasculature
  • Role in structural stability of vessel wall
  • Endothelial cells associated with pericytes are more resistance to apoptosis than isolated endothelial cells
    1. Indicates sole of PC in structural integrity & genesis of the BBB
  • Phagocytic activity

Astrocyte end feet

  • Star shaped glial cells
  • Provides biochemical support for BMEC
  • Influence of morphogenesis & organization of vessel wall
  • Factors released by astrocytes involved in postnatal maturation of BBB
  • Direct contact between endothelial cells & astrocytes necessary to generate BBB.
  • Co-regulate function by the secretion of soluble cytokines such as (LIF, leukemia inhibiting factor), Ca2+ dependent signals by intracellular IP-3 & gap junction dependent pathways, & second messenger pathways involving extracellular diffusion of purinergic messenger.

Regions of the brain not enclosed by BBB

  • Circumventricular organs
    1. Area postrema, the “vomiting centre” of the brain
    2. Median eminence, regulates the anterior pituitary through the release of neurohormones
    3. Neurohydrophysis, detects levels of oxytocin & ADH in the blood
    4. Pineal gland, secretes melatonin & is associated with circadian rhythms
    5. Subfornical organ, regulates body fluids, fluid & electrolyte imbalance
    6. Lamina terminalis, part of it detects peptides

These are regions which need to respond to factors present in systemic circulation.

Normal BBB transport:

  • Simple & facilitated diffusion
  • Facilitated transport by carrier systems
  • Receptor mediated endocytosis
  • Paracellular transfer more common than transcellular transfer

Diffusion

  • Phospholipid bilayer
  • Movement of substances down diffusion gradient
  • Transfer of lipophilic substances
    1. Alcohol, nicotine, oxygen, carbon dioxide


Facilitated transport

  • Carrier systems
    1. Particular essential amino acids, glucose, these are extremely specific
      • Transport D-glucose only
      • Large neutral amino acids which act as precursors for neurotransmitters
      • Only those which the brain cannot make
      • Glycine: it can block the transmission of nerve signals, hence special carrier which ensures that glycine can be removed from brain
  • Receptor mediated endocytosis
    1. Leptin, insulin, overlaps with carrier systems

Transfer of microbes across BBB

  • Physical damage of BBB
  • Ligand receptor interactions followed by host cell actin cytoskeletal rearrangements
  • Transcellular transport while maintaining integrity of BMEC

Physical damage of the BBB

  • Microhemorrhage or necrosis of surrounding tissue
  • Mechanical obstruction of microvessels by parasitized red blood cells (PRBC), platelets or leukocytes in cerebral malaria.
  • Overproduction of cytokines Borrelia bugdoferi: fibrinolytic system linked by activation cascade may lead to focal & transient degradation of tight junction proteins

Ligand receptor interactions followed by host cell actin cytoskeletal rearrangements

  • E-Coli binding to BMEC type I fimbriae, outer membrane protein A, Ibe proteins, cytotoxic necrotizing factor 1 (CNF1)
  • S. pneumonia cell wall phosphorylcholine & BMEC platelet activating factor receptor

Microbe-specific interactions with BBB

  • Bacteria
    1. Bind to BMEC, invade BMEC, induce actin cytoskeletal rearrangement, traverse BBB as live bacteria
  • Mycrobacteria
    1. Unclear, although DNA microarray results show that gene expression profile of M. tuberculosis associated with human BMEC showed at least 33 genes that were 8X or more upregulated & 147 genes that were 8X or more downregulated
  • Spirochetes & Fungi
    1. Largely unknown, poorly understood: they´re able to bind, be internalized & traverse human BMEC without obvious change in integrity of BMEC.