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1 Embryological Origins oftheUpper andLower Respiratory Tract
11
stage, the epithelium of the primitive airways begins to proliferate and differentiate
from proximal to distal regions [42]. In this stage, the tubes forming the airways are
lined with high columnar epithelium. Neuroendocrine, ciliated, and goblet cells
begin to emerge, while mesenchymal cells initiate the formation of cartilage and
smooth muscle cells. Cuboidal cells in the distal region start to differentiate by
accumulating glycogen. Glycogen serves as a source of energy for cell differentiation and later becomes a crucial component of surfactant, which will cover the
respiratory pathways. The distal cuboidal cells represent immature type 2 alveolar
epithelial cells. After this stage, the entire conducting airway tree, comprising 20
generations, has developed, and vascularization has occurred.
1.2.4.3 Canalicular Stage
The main events observed during the period spanning weeks 16–25 of gestation
include the initiation of the air–blood barrier formation and surfactant secretion.
Bronchioles emerge in this stage, and the lumens of bronchi and bronchioles expand,
accompanied by increased vascularization [27]. By the 20th week, cuboidal epithelium differentiates into type 1 and type 2 cells. Type 1 epithelial cells cover the
majority of the alveolar surface, including the air–blood barrier. Type 2 epithelial
cells store surfactant with their intracellular storage organelles called lamellar bodies [43]. Therefore, they are crucial for lung function. As a consequence of the
expansion of distal air sacs, cuboidal epithelium begins to atten, giving rise to
regions with a thin air–blood barrier. Subsequently, the attened epithelial cells
come into contact with the capillaries. During this period, pulmonary vascular
development encompasses increased capillary proliferation and characterization
around airspaces in peripheral mesenchyme. Despite the contact of capillaries with
the epithelium, it is not until the 23rd week that capillaries approach and reach their
closest proximity to the alveolar epithelium [44]. The capillaries beneath the epithelial cells atten and differentiate into type 1 epithelial cells.
1.2.4.4 Saccular Stage
It is the stage spanning weeks 24–38 of gestation during which the vital functions
required for the fetus to survive are established. In this phase, primary terminal air
sacs are formed, and surfactant secretion from type 2 cells occurs. At the onset of
the saccular stage, the airways terminate in thin-walled terminal sacs. Subsequently,
these sacs give rise to alveolar ducts and alveolar sacs. Production of surfactant
begins around the 26th week of gestation and continues gradually throughout the
lung parenchyma [45]. The secretion of surfactant into the lumen of the airways
occurs around the 30th week of gestation.
By covering the alveolar surface, surfactant reduces the surface tension at the
air–liquid interface, thereby facilitating lung expansion in the postnatal period.
During the canalicular and saccular stages, blood vessels grow both longitudinally
and transversely. Additionally, during the saccular stage, fetal cortisol concentration
increases, which is critical for postnatal lung respiration. Cortisol contributes to
surfactant synthesis, tissue remodeling, and differentiation of alveolar epithelial
cells [46].
12
Ş. D. Yüksel et al.
1.2.4.5 Alveolar Stage
During this stage, the newly formed sacs continue to develop through a process
called alveolarization, which starts at birth and continues until the third year of
postnatal life. This process commences around the 36th week of gestation and
extends up to 3 years after birth. These air sacs are divided by septa, leading to the
formation of alveoli. The septa comprise myobroblasts, lipobroblasts, endothelial cells, and pericytes [26].
In addition to the division of alveolar ducts into terminal alveoli, this stage also
involves pulmonary angiogenesis to maximize the lung surface area for gas
exchange. While the formation of airways is completed by birth, the shaping of the
parenchyma occurs during the postnatal period.
It is now widely accepted that over 85% of alveoli are formed after birth. This
means that the mammalian lung is not fully mature at birth. Therefore, this stage is
referred to as the alveolar stage. The primary mechanism responsible for this is the
connective tissue that divides the alveolar sacs, known as septa. Initially thick, these
septa gradually become thinner over time [47].
1.2.5 Congenital Respiratory System Defects
The diagnosis and treatment of congenital lung malformations have shown signicant advancements in the last decade. Progress in imaging technologies has enabled
earlier and more accurate diagnoses, consequently facilitating timely interventions
in utero or, when necessary, after birth. These developments have raised survival
rates from 60% to 95% [48].
1.2.5.1 Tracheal Agenesis
Tracheal agenesis is extremely rare, occurring in 1in 50,000 to 1in 100,000 live
births, and it often leads to fatal outcomes. The cervical trachea is typically absent,
and the bronchus or carina is connected to the esophagus. It is classied into three
types [49]. Type 1 represents 20% of cases, with upper tracheal agenesis. The bronchi are normal, and there is a tracheoesophageal stula. Type II, which is the most
commonly observed type, accounting for 60% of cases, involves complete tracheal
agenesis. The bronchi are normal, and a stula exists between the carina and the
esophagus. In Type III, the bronchi arise separately from the esophagus.
The presence of the tracheoesophageal or bronchoesophageal stula is crucial
for the life-saving treatment of critically ill newborns with tracheal agenesis, as it
allows for esophageal intubation and mechanical ventilation [50].
1.2.5.2 Congenital Tracheal Stenosis
Congenital tracheal stenosis (CTS) is a rare condition with an estimated incidence
of 1in 64,500 births. CTS involves a true embryological abnormality of the tracheal
skeleton, characterized by the presence of complete tracheal rings instead of half
rings along the stenotic segment and the determination of a xed narrow tracheal
lumen. Surgical intervention is often required for its management [51].
1 Embryological Origins oftheUpper andLower Respiratory Tract
13
1.2.5.3 Lung Agenesis
Agenesis of one or both lungs is the absence of development of one or both lungs, a
condition that is highly rare. It emerges due to the failure of respiratory buds to
develop. Unilateral lung agenesis is more common than bilateral lung agenesis [52].
Unilateral lung agenesis does not necessarily impair the individual’s ability to sustain life.
1.2.5.4 Lung Hypoplasia
Congenital diaphragmatic hernia (CDH) is a rare birth defect characterized by
incomplete development of the diaphragm, resulting in the herniation of abdominal
organs into the chest cavity. It leads to cardiorespiratory developmental anomalies.
One of these anomalies, impaired lung development (pulmonary hypoplasia), is
characterized by compromised branching morphogenesis, immature pulmonary
epithelium and mesenchyme, and a signicant reduction in alveolar units, all of
which contribute to impaired gas exchange. In high-income countries, the mortality
rate among CDH patients has remained around 20–30% since the 1990s; however,
in low- and middle-income countries, the mortality rate can exceed 90%. CDH
treatment disproportionately consumes healthcare resources compared to other conditions affecting full-term infants that require complex, multidisciplinary neonatal
intensive care [53].
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15
Histological Characteristics oftheUpper
Respiratory Tract: Continuum
withLower Respiratory Tract
ElginTurkozUluer, MuhammedYusufPekmezci,
RalphEpaud, andMahmudKemalOzbilgin
2.1 Introduction
The respiratory system is responsible for the process of respiration, from the initial
inhalation in the nasal passages to the nal exchange of oxygen and carbon dioxide
in the alveoli of the lungs. Its core function includes transporting, purifying, and
enabling the exchange of these gases, crucial for supporting cellular metabolism.
The circulatory system collaborates closely to distribute oxygen to body cells and
remove carbon dioxide.
In addition to its primary role, the respiratory system contributes to vocalization
and the sense of smell. It has an endocrine function, produces hormones, and aids in
immune responses. The system comprises three key components: air conduction
passages, the respiratory area, and motor structures, supported by mucosal linings
and structural elements.
As air travels toward the alveoli, it undergoes heating, humidication, and purication facilitated by specialized respiratory mucosa. This mucosa, consisting of
various cell types, traps and removes particles, preventing them from reaching the
alveoli. The system’s multifaceted functions, including vocalization, make it essential for sustaining life and overall well-being.
2
E. T. Uluer (*) · M. Y. Pekmezci · M. K. Ozbilgin
Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar
University, Manisa, Turkey
R. Epaud
Service de Pédiatrie Générale, Centre Hospitalier Intercommunal de Créteil, Créteil, France
Univ Paris Est Creteil, INSERM, IMRB, Créteil, France
Centre des Maladies Respiratoires Rare, Respirare®, Créteil, France
e-mail: ralph.epaud@chicreteil.fr
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2024
H. Yüksel et al. (eds.), Pediatric Airway Diseases, Comprehensive ENT,
https://doi.org/10.1007/978-3-031-74853-0_2
17
18
E. T. Uluer et al.
2.2 Nasal Cavity
The nose is partitioned into two nasal cavities, distinguished as right and left, by a
central area comprising cartilage and bone. The anterior portion of each cavity is
enlarged and establishes a connection with the external environment via the anterior
naris or nostrils. The posterior part of the nasal cavity is adjacent to the nasopharynx, the superior section of the pharynx, through the posterior naris. The front wall
of the anterior naris is constructed of brous connective tissue and cartilage. Except
for the anterior naris, each nasal cavity is enclosed by a solid barrier formed of bone
and hyaline cartilage. In the lateral bony walls, three conchae (superior, medial, and
inferior) are present. Each nasal cavity is further divided into three sections: the
vestibule, located directly behind the anterior naris, as well as the respiratory and
olfactory regions.
2.2.1 Vestibule
The external surface of the nose is covered by the skin with a stratied squamous
epithelium. This skin, distinguished by the presence of large sebaceous glands,
extends into the front section of the vestibule. Within this area, both sebaceous and
sweat glands exist, along with thick hairs known as vibrissae. These hairs function
to eliminate large particles from the inhaled air. The secretions from the sebaceous
glands in the vestibule aid in trapping these particles. Collagen bers connect the
dermis of the vestibule to the perichondrium of the hyaline cartilage. Deeper within
the vestibule, the epithelium transitions into respiratory epithelium, and sebaceous
glands are not observed in this region.
2.2.2 Respiratory Mucosa
The nasal cavity is covered by the respiratory mucosa, which is a type of pseudostratied ciliated columnar epithelium. Within the underlying layer called lamina
propria, there are mucous glands and serous crescents situated beneath the basal
lamina. This lamina propria extends into the surrounding periosteum or perichondrium, which encases the bone or cartilage tissues adjacent to it. In the middle portion of the nasal cavities, the surface is relatively smooth, but there are folds on
lateral walls called turbinates or conchae. These turbinates serve to enlarge the surface area and are covered by the respiratory epithelium. The presence of these turbinates induces air turbulence, leading to improved warming of the air and increased
interaction of particles with the mucous membrane. Among these turbinates, the
largest one is the inferior turbinate, which possesses a thicker mucous membrane.
Extensive networks of interconnected veins are located within the lamina propria of
the lower and middle turbinates. These venous plexuses contribute to air warming,
and the autonomic nervous system is responsible for regulating and controlling this
process.
2 Histological Characteristics of the Upper Respiratory Tract: Continuum with Lower…
19
2.2.3 Olfactory Mucosa
The olfactory mucosa is a small region situated in the upper part of the nasal cavities
and contiguous lateral and medial nasal walls. This mucosa is coated with pseudostratied columnar epithelium; however, it lacks goblet cells within the epithelial
layer, and a clearly discernible prominent basal lamina cannot be identied. The
yellow-brown pigment found in the olfactory mucosa stands out under a microscope
due to its coloration. Within the olfactory epithelium, there exist four distinct cell
types: supporting cells, basal cells, olfactory receptor cells, and brush cells.
2.2.3.1 Cells ofOlfactory Mucosa
Supporting Cells
Supporting cells are the most numerous cells within the olfactory epithelium. It
features a narrow base and a wide, prismatic-shaped apical region, measuring
around 50–60μm in length. The nucleus, which is oval and rich in heterochromatin,
is positioned in the upper apical third of the cell. This distinct placement aids in
easily distinguishing these cells from others. Numerous microvilli are present on the
apical surface. The apical cytoplasm contains yellow pigment granules and a substantial number of mitochondria, contributing to the distinctive coloration of the
olfactory epithelium. Abundant tonobrils, a signicant presence of rough endoplasmic reticulum (rERs), and a lesser amount of smooth endoplasmic reticulum
(sERs) are observed in the cytoplasm.
These cells are linked to neighboring olfactory cells through adherence-type
junction complexes, although gap and tight junction complexes are not evident. The
role of support cells parallels that of glial cells within the central nervous system.
They enwrap mature olfactory cells, ensuring electrical isolation. Additionally, they
form connections with each other through tight junction complexes, establishing a
barrier in the apical region. This network of support cells provides both mechanical
and metabolic support to olfactory nerve cells. Also, these cells synthesize and
secrete “odorant binding proteins,” which are small and water-soluble proteins.
Basal Cell
Basal cells are stem cells and progenitors of the other mature cell types. The cells
are small, rounded cells and form an irregular single row along the basal membrane,
without extending toward the lumen. Their cytoplasm contains an abundance of lamentous structures, while the nucleus, stained with a darker shade, assumes an oval
shape, and is located in the lower region of the olfactory cell nuclei. Basal cells
encompass the initial segment of olfactory nerve axons. Their cytoplasm contains
relatively few organelles [1].
Olfactory Receptor Cell (Bipolar Neuron)
It is typically situated in the lower two-thirds of the epithelial layer, positioned
between supporting cells. The protrusion on the outer (apical) side is short, resembling a dendrite, while the inner (basal) extension is lengthy, like an axon, dening
20
E. T. Uluer et al.
the bipolar nature of this neuron. Neurobrils can be discerned in the cytoplasm due
to their silver appearance. The circular nucleus resides beneath the supporting cells.
This neuron spans from the base membrane to the cavity, enveloped by supporting
cells. The dendrites that extend into the nasal cavity measure 0.5μm in thickness
and 200μm in length.
The olfactory cells have a single dendrite that projects toward the cavity and
exhibits small bulges referred to as olfactory vesicles. These vesicles each sprout
about 6–10 cilia that project in various directions, collectively forming a mesh-like
structure on the upper surface. These cilia are anchored to basal bodies within the
olfactory vesicle and extend radially in parallel to the mucosal surface. Airborne
odor molecules dissolve in the mucus layer upon entering the respiratory tract. By
binding to the odor-binding proteins, these molecules transport to the olfactory
receptors on the plasma membrane of the cilia and then trigger an action potential.
This electrical signal then travels through the incredibly thin (0.2μm) basal extensions (axons) of the olfactory cells.
Upon leaving the epithelium, these axonal extensions pass through the lamina
propria and approximately 20 of them come together to create the visible “olfactory
la.” Although these nerve bers lack a myelin sheath. Schwann cells envelop them
after departing from the epithelial layer. This unique property of Schwann cells
guides the formation of new synapses during cell regeneration, as described by
Nomura etal. [2].
The olfactory la traverse the lamina cribrosa of the ethmoid bone and establish
connections with sensory neurons in the olfactory bulb. The lifecycle of olfactory
cells lasts around 1 month, and these neurons are among the few types in the human
body capable of proliferation.
Brush Cell (Microvillar Cell)
The primary distinguishing characteristic of these cells is the existence of prominent microvilli on their upper surfaces. The lower surface of these cells extends
toward the basal lamina. These cells are present in limited numbers in the olfactory
epithelium.
There are two distinct types of these cells. Type I brush cells function similar to
absorptive cells seen in the digestive and respiratory epithelium and their nuclei are
aligned with the nuclei of the supporting cells. They are in smaller numbers compared to Type II cells. Some have even proposed that type II cells constitute a new,
fth cell type within the olfactory mucosa. Type II cell nuclei are situated above the
nuclei of supporting cells and lack brush-like border characteristics.
Research has demonstrated their robust activity of Na+, K+-ATPase on the lower
surface, indicating their role in cellular transport. It is posited that type II cells
potentially play a role in generating and upholding the distinct structure of the
mucus layer that coats the olfactory mucosa, as outlined by Asan and Drenckhahn [3].
2.2.3.2 The Lamina Propria
The lamina propria of the olfactory epithelium is rmly attached to the periosteum
and comprises loose connective tissue that has abundant capillaries, veins, and
2 Histological Characteristics of the Upper Respiratory Tract: Continuum with Lower…
lymphatic vessels. Within the lamina propria, unmyelinated bers of the olfactory
nerve coexist with myelinated nerve bers. Lymphatic vessels within this region are
connected to the subarachnoid space in the brain through capillaries that course
within the olfactory la. Consequently, infections originating in the nasal mucosa
can potentially spread to the meninges.
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2.2.3.3 Olfactory Glands (Bowman’s Glands)
Olfactory glands are branched tubuloalveolar glands situated in the lamina propria
and are composed of serous acini. The secretory ducts of these glands are lined with
cubic cells and traverse through the epithelium to reach the surface. This conguration enables the excretory duct cells to be visible in the olfactory epithelium, as
discussed by Nomura etal. Similar to sustentacular cells, the gland cells contain
lipofuscin granules. Excretory ducts exhibit similarity to acinar cells in the basal
portion of the epithelium, appearing as slender cells surrounded by connective tissue in the upper portion of the epithelium. Bowman’s glands constantly produce
secretions that clean the apical surfaces of olfactory cells and facilitate the reception
of new stimuli. These secretions from the glands also contain immunoglobulin A
(IgA) and lysozyme, both of which are produced by plasma cells situated in the connective tissue enveloping the gland [4, 5].
2.3 Paranasal Sinuses
Paranasal sinuses are air-lled cavities located within the ethmoid, sphenoid, maxillary, and frontal bones. These spaces are interconnected with the nasal cavity. The
mucous membrane that covers these sinuses is tightly attached to the periosteum.
The mucosal surface of the sinuses is lined with a respiratory epithelium. However,
this epithelium is thinner and contains many Goblet cells. The underlying lamina
propria is composed of loose connective tissue abundant in blood vessels, and it
contains a limited number of small seromucous glands. The mucus produced
through ciliary activity is expelled into the nasal passages. The epithelium that lines
the paranasal sinuses, nose, and nasopharynx is coated with a layer of mucus. This
mucus layer is in constant motion toward the oropharynx due to the coordinated
movement of kinocilia.
2.4 Pharynx
The pharynx is composed of three distinct segments. The upper section, which
connects to the nasal cavity, is referred to as the nasopharynx; the middle portion,
which opens into the mouth, is known as the oropharynx; and the lower part that
connects to the larynx is termed the laryngopharynx. The lining epithelium of the
pharynx is primarily the respiratory epithelium, but there exists a small region of
stratied squamous epithelium (oral mucosa) on the posterior wall where it contacts the soft palate. The lamina propria, a loose connective tissue layer, is rich in