Histology, Respiratory Epithelium
Nakisa Kia'i
Introduction
The respiratory system is constantly filtering through the external environment as humans breathe
air. The airways must maintain the ability to clear inhaled pathogens, allergens, and debris to
maintain homeostasis and prevent inflammation.
The respiratory system subdivides into a conducting portion and a respiratory portion. The majority
of the respiratory tree, from the nasal cavity to the bronchi, is lined by pseudostratified columnar
ciliated epithelium. The bronchioles are lined by simple columnar to the cuboidal epithelium, and the
alveoli possess a lining of thin squamous epithelium that allows for gas exchange.
Structure
There are four main histological layers within the respiratory system: respiratory mucosa, which
includes epithelium and supporting lamina propria, submucosa, cartilage and/or muscular layer and
adventitia. Respiratory epithelium is ciliated pseudostratified columnar epithelium found lining most
of the respiratory tract; it is not present in the larynx or pharynx. The epithelium classifies as
pseudostratified; though it is a single layer of cells along the basement membrane, the alignment of
the nuclei is not in the same plane and appears as multiple layers. The role of this unique type of
epithelium is to function as a barrier to pathogens and foreign particles; however, it also operates by
preventing infection and tissue injury via the use of the mucociliary elevator.
The Conducting Portion
The conducting piece of the respiratory system consists of the nasal cavity, trachea, bronchi, and
bronchioles. The luminal surfaces of this entire portion have a lining of ciliated pseudostratified
columnar epithelium and contain goblet cells. Their role is to secrete mucus that serves as the first
line of defense against incoming environmental pathogens. Cilia move the mucus-bound particulate
up and away for expulsion from the body. The various types and abundance of cells are dependent on
which region of the airway they are.[1]
In the most proximal airway, hyaline cartilage rings support the larger respiratory passages, namely,
the trachea and bronchi, to facilitate the passage of air. Three major cell types are found in this
region: ciliated, non-ciliated secretory cells, and basal cells.
Ciliated cells, each lined with 200 to 300 cilia, account for more than half of all epithelial cells in the
conducting airway. As the degree of branching within the airway tree continues, the epithelium
gradually changes from pseudostratified to simple cuboidal; and the predominant cells become nonciliated cells, Clara cells.
The Gas-Exchange Portion
The respiratory or gas-exchange region of the lung is composed of millions of alveoli, which are lined
by an extremely thin, simple squamous epithelium that allows for the easy diffusion of oxygen and
carbon dioxide. Additionally, cuboidal, surfactant-secreting cells, Type II pneumocytes, are also
found lining the walls of alveoli. Surfactant, which is primarily composed of
dipalmitoylphosphatidylcholine, has a vital role in lowering the surface tension of water to allow for
effective gas exchange.[1]
Type I pneumocytes are flattened cells that create a very thin diffusion barrier for gases. Tight
junctions are found connecting one cell to another.[2] The principal functions of Type I pneumocytes
are gas exchange and fluid transport. Type II Pneumocytes secrete surfactant, which decreases the
surface area between thin alveolar walls, and stops alveoli from collapsing during exhalation. These
cells connect to the epithelium and other constituent cells by tight junctions. Type II pneumocytes
also play a vital role in acting as progenitor cells to replace injured or damaged Type I
pneumocytes.[3]
Function
Just as the skin protects humans from external pathogens and irritants, the respiratory epithelium
acts to protect and effectively clear the airways and lungs of inhaled pathogens and irritants.
The division of the respiratory system into conducting and respiratory airways delineates their
function and roles. The conducting portion, consisting of the nose, pharynx, larynx, trachea, bronchi,
and bronchioles, which all serve to humidify, warm, filter air. The respiratory portion is involved in
gas exchange. There are three major types of cells found in respiratory epithelium, and each holds a
vital role in regulating how humans breathe. If any of these components of the barrier are not
properly functioning, the body becomes susceptible to acquiring infections, pathogens or inducing
inflammation, and disturbing hemostasis.
Humidification & Warming
Humidification requires serous and mucous secretions, and warming relies on the extensive capillary
network that lays within the alveoli. The alveoli are also extensively enveloped by capillaries that
allow for air to be conditioned and heated by the vascular plexus that surrounds them and provides
for heat-exchange. The branching of the arteries and veins of the pulmonary system follow a similar
branching pattern to that of the airway tree. The walls of the pulmonary arteries and veins are more
delicate than the vasculature in other regions of the body, as the pulmonary circulation functions at a
lower pressure than the systemic circulation.
Filtration
Filtration occurs by the trapping mechanism of mucus secretions and ciliary beating. This process
allows trapped particulate to move towards the throat where mucus is swallowed or expelled by the
body.
Goblet cells are columnar epithelial cells that secrete high molecular weight mucin glycoproteins into
the lumen of the airway and provide moisture to the epithelium while trapping incoming particulate
and pathogens. In a healthy airway, ciliated cells are columnar epithelial cells that are modified with
hundreds of hair-like projections, beating at a rapid frequency of approximately 8 to 20 Hz,
mobilizing the mucus that is found resting on it.[4]
Oxidant defense & Response to Injury
Cells found in the respiratory epithelium are continually fighting off inhaled particulate and
pathogens and regenerating themselves after injury. Basal cells, which are small, nearly cuboidal cells,
attached to the basement membrane by hemidesmosomes, can differentiate into other cell types
found within the epithelium. Basal cells provide an attachment site for ciliated and goblet cells to the
basal lamina. They also respond to injury and act in oxidant defense of the airway epithelium and
transepithelial water movement.
Gas Exchange
Within the hundreds of millions of microscopic alveolar sacs, the exchange of oxygen for carbon
dioxide occurs. Inhaled air diffuses through the alveoli into the pulmonary capillaries, and at the same
time, carbon dioxide from deoxygenated blood diffuses into the capillaries then into the alveoli and is
expelled through the airways as exhalation occurs.
Microscopy Light
Light microscopy of hematoxylin and eosin (H&E) stained samples of respiratory tissue reveals
pseudostratified epithelium. The term “pseudostratified” is given to this type of epithelium as it
appears to be stratified, but all of the component cells are actually attached to one underlying
basement membrane. Nuclei appear at varying levels, causing the appearance of stratified epithelium.
With H&E staining viewed under light microscopy, the basement membrane appears as a clearly
delineated pink line.[5] Goblet cells, with mucinogen granules, also are found scattered amongst the
epithelium, and basal cells are present at the basal aspect of the epithelium, acting as progenitor cells
for other cell types. The cells that reach the free or apical surface of the epithelium are ciliated,
appearing with thin, ‘hair-like’ projections. Each cilium is given rise to by a basal body, which appears
as a dense eosinophilic line.[6]
The epithelium of the trachea will appear as a narrow pink-staining region immediately basal to the
epithelium as a result of its unusually thick basement membrane. Outside the connective tissue layers,
rings of C-shaped cartilage keep the lumen of the trachea patent. The transition from the trachea to
bronchi is made apparent by the appearance “plates” instead of C-shaped hyaline
rings.[7] Additionally, a layer of smooth muscle is present between the lamina propria and
submucosa.[7]
The bronchioles can be differentiated from the bronchi by the absence in cartilaginous structures and
the absence of glands. The transition to respiratory bronchioles shows by the presence of alveoli in
their walls and the gradual reduction of the height of epithelium. Clusters of alveoli, called alveolar
sacs, become visible, appearing as small knobs of smooth muscle, elastic fibers, and collagen.
Microscopy Electron
Electron microscopy (EM) can be used to visualize individual cell types and ultrastructural features of
epithelium found within respiratory tissue samples. At the level of the trachea and tracheal lining,
electron microscopy delineates the different cell types: basal cells, goblet cells, and ciliated cells, as
well as their associated organelles and cytoplasmic components. Ciliated epithelium with microvilli
are seen well under EM, a cross-section of cilia allows for visualization of the typical 9+2
arrangements of microtubules within the cytoplasm.[4]
The level of the alveolus reveals the extremely thin air-blood barrier made up of Type I pneumocytes,
capillary endothelium, and the fused basal lamina.[8] Additionally, Type II pneumocytes are seen
distinctively from the more thin, delicate Type I pneumocytes. Type II cells contain lamellar bodies,
rough endoplasmic reticulum, Golgi and reticular fibers, as well as microvilli.
Pathophysiology
A number of diseases affect the respiratory system, which may be due to some degree of defective
barrier function, a genetic mutation or an inflammatory process. The following discussion outlines a
few major diseases that affect respiration. Though not comprehensive, the importance of the proper
functioning of the respiratory system and what occurs when a component is malfunctioning may be
appreciated based on the few selected diseases discussed below.
Asthma
Asthma is an inflammatory disease that results in remodeling of the airway walls and causes a
hyperreactivity response from environmental triggers, with the overproduction of mucus.[9] Asthma
is a common and chronic health condition that affects both adults and children. The incidence is
increasing and poses a strong concern for the impacts on health, economic burden, and
environmental quality.[10]
The cause of asthma is inflammation and edema of the airway that results in bronchospasms that
block air entry into the lungs. It may be triggered by environmental factors such as dust, pollen,
debris, and pathogens. The response to such triggers is bronchoconstriction, a process in which
smooth muscle tightens and narrows the caliber of the bronchi and bronchioles, resulting in wheezing
and shortness of breath. Bronchoconstriction occurs through a series of complex interactions between
the mucosal epithelium, mast cells, smooth muscles, and the parasympathetic nervous system.[11]
Cystic Fibrosis
Cystic fibrosis is a disease that once had a life expectancy of a few months and now has a median
lifespan of about 40 years.[12] It requires early diagnosis and optimized, mutation-specific treatment
to maintain a quality of life for patients. Cystic fibrosis is an autosomal recessive pathology caused by
a mutation in the cystic fibrosis transmembrane conductance regulator gene, CFTR, most commonly
the phe508del gene.[13] CFTR protein functions as an ion channel that regulates the amount of liquid
through the secretion of chloride and inhibition of sodium absorption from exocrine glands. Chloride
and bicarbonate transport play a role in regulating the thickness of the epithelial lining fluid,
maintaining pH and sensing the presence of incoming pathogens or irritants. When uncontrolled, the
increased sodium reabsorption causes water to follow and results in thick mucus secretions in nearly
every organ system.[13] Though thousands of mutations of the CFTR have been described, each
mutation manifests with varying effects on the gene and can result in differing phenotypic
manifestations in patients, some resulting in more mild disease, others in much more severe
prognosis. Cystic fibrosis may affect multiple organ systems, from the lungs to the digestive tract, the
pancreas, the liver or the reproductive organs.[14]
In the majority of patients, Cystic fibrosis leads to chronic, progressive lung disease and eventually
death. Recurrent and infectious exacerbations lead to structural changes and damage to the
respiratory system. These complications, in turn, dictate the treatment goals for this condition; to
improve mucociliary clearance and to reduce the frequency of bacterial infections while aiming to
enhance the quality of life.[12]
Ciliary Dyskinesia
The respiratory system relies heavily on the ability of cilia to move mucus and inhaled materials up
into the proximal airways and away from the lower respiratory tract. Primary ciliary dyskinesia
(PCD) often presents with situs abnormalities, chronic sinus or pulmonary diseases, and abnormal
sperm motility. Ciliary movement plays a role in many organs of the body. When impaired, this
manifests in several organ systems. In the respiratory system, impaired mucociliary clearance occurs
and results in recurrent infections of the sinuses, ears, and lungs. In the reproductive tract, both
sperm motility from flagellae and the fimbriae of fallopian tubes are affected and often lead to
infertility. Situs invertus occurs as a result of defective cilia during embryogenesis, as normal
functioning cilia are required in the visceral rotation of organs.[4]
The diagnosis of PCD, though complex and often missed or misdiagnosed, frequently involves
analysis of cilia at an ultrastructural level and molecular genetic testing with one of the 33 genes
associated with PCD.[15] The triad of chronic sinusitis, bronchiectasis, and situs invertus, resulting
from ciliary dyskinesia are known as Kartagener syndrome.[4]
Clinical Significance
The clinical significance of respiratory diseases in the context of histology and function is a complex
and broad topic. There is a multitude of conditions and diseases that involve the respiratory system.
Below is a list of diseases involving the respiratory system and its constituents. An understanding of
the microanatomy and functioning of the respiratory system is key to the mechanism of each of the
diseases listed below.
Bronchial Diseases
Asthma
Bronchiectasis
Bronchitis
Bronchopneumonia
Tracheobronchomalacia
Bronchogenic cyst
Ciliary Motility Disorders
Kartagener syndrome
Laryngeal Diseases
Laryngitis
Laryngomalacia
Vocal cord paralysis
Neoplasms
Lung Diseases
Acute chest syndrome
A-1 antitrypsin deficiency
Cystic fibrosis
Hemoptysis
Pulmonary hypertension
Lung abscess
Neoplasms
Pneumonia
Pulmonary edema
Pulmonary embolism
Atelectasis
Tuberculosis
Pleural Diseases
Chylothorax
Hemothorax
Hydrothorax
Pleural effusion
Tuberculosis, pleural
Infections
Neoplasms
Review Questions
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