About ⅔ of the anterior vestibule and nostrils are covered by skin, containing large stiff hair called vibrissae that guard the entrance into the nasal cavity by collecting airborne dust and bacteria. About ⅓ is covered by a squamous epithelium anteriorly, followed by transitional epithelium (Fig. ).
The structure of a squamous (left) and transitional (right) epithelium.
In the remainder of the nasal cavity there are mainly two types of epitheliums [12
]. The main epithelium is a typical respiratory epithelium also called Schneiderian membrane, ciliated pseudostratified columnar epithelium with goblet cells scattered throughout, lining most of the respiratory tract and the sinuses. The second is the olfactory epithelium, a chemoreceptive type of epithelium which is thinner and only found in the upper part of the nose and the vomeronasal organ. Another type of tissue may also be found in the nasal cavity, which is the lympoid tissue, where occasional M-cells or M-cell clusters (lymph corpuscles) may be found in the epithelium. Their main density is posterior in the adenoid tissue. The epithelium covering the paranasal sinuses is similar to respiratory mucosa, but less vascular, thinner, and more loosely attached to the bony walls [11
The nasal epithelium rests on a well defined layer between the epithelium and the connective tissue, made of tissue fibrils or collagen fibrils, called basement membrane. The epithelial cells are anchored to this extracellular matrix. The underlying connective tissue is called lamina propria, a tissue containing dense network of fenestrated capillaries, supplying the tissue with large volume of blood, which drain directly into the systemic circulation, avoiding first pass metabolism for compounds entering the body through the nasal route [41
]. The lamina propria also prevents the epithelium from dehydration due to numerous small glands (and the goblet cells embedded in the epithelial sheet) producing serous and mucous secretions for the epithelium [42
]. Their production keeps the epithelial surface moist and provides a fluid sheet that traps foreign materials. The ciliated cells then move the moist sheet or the mucus, as a whole, the beating of the cilia being unidirectional. The basement membrane is thickened in patients with rhinitis [43
]. In the olfactory region, the lamina propria is directly contiguous with the periosteum of the underlying bone and contains numerous lymphatic vessels, unmyelinated olfactory nerves, myelinated nerves, olfactory glands (branched tubuloacinar serous glands) in addition to dense network of capillaries.
The mucosal membrane is thickest over the conchaes and the center of the septum due to highly vascularised mucosa which is also linked to the erectile tissue in the nose, particularly in the middle and inferior chonchae as shown in (Fig. ), which enables the airways to widen or narrow. This autonomically controlled vasculature of the nasal tissue, in combination with its rich supply of secretory cells is of importance in the modification of inspired air.
The olfactory epithelium is found in the olfactory region of the nose and in the vomeronasal organ. This part of the nasal cavity is specialized for chemoreception, it is also ciliated, but they are far less numerous than in the respiratory region and there are no goblet cells in that region. There are five cell types present there, where one is chemoreceptive. As in the respiratory region, there are serous glands in the lamina propria under the olfactory region called olfactory glands or the Bowmanns glands. Secretions from these clean the sensory structures and ready them for reuse. They secret aqueous non-viscous fluid that has appropriate characteristics to solubilise substances for olfaction and clean the olfactory cilia between smells.
The nasal mucosal consists of seven types of cells, (Table
), where four of them are found in the respiratory region and other five in the olfactory region. Their density and distribution differs greatly from one region of the nose to another [16
The ciliated cells (Fig.
) are the most frequent cell type in the nasal cavity, their function is e.g. to provide a coordinated sweeping motion of the mucus coat to the throat, called ciliary escalator or ciliary clearance. This function is an important protective mechanism for removing mucus and trapped inhaled particles. Due to this clearance, inhaled drugs have a short window to be absorbed, otherwise they will be cleared to the throat and swallowed. Numerous mitochondria are found in the cytoplasm in the apical part, as signs of an active metabolism. All ciliated cells are covered with about 300 microvilli, which are fingerlike cytoplasmic expansions on the surface of the cells in addition to the cilia. These microvilli are uniformly distributed on the entire apical surface [16
], increasing the surface area significantly. The microvilli also prevent drying of the surface by retaining moisture essential for ciliary function.
The anatomy of a ciliated cell and schematic diagrams showing the molecular structure of cilia.
Each ciliated cell contains about 100-250 mobile cellular appendage called cilia, 0.3 µm wide and 5 µm in length as shown in (Fig. ). Their function is to help transporting fluid or the carpet of mucus towards the throat where after it is swallowed. The cilia contain a motor protein called dynein and microtubules, which are composed of linear polymers of globular proteins called tubulin. The core of each of the structures is termed the axoneme and contains two central microtubules that are surrounded by an outer ring of nine doublet microtubules. One full microtubule and one partial microtubule, the latter of which shares a tubule wall with the other microtubule, comprise each doublet microtubule. The dynein molecules are located around the circumference of the axoneme at regular intervals along its length where they bridge the gaps between adjacent microtubule doublets. Dynein, the motor protein, uses the energy of adenosine triphosphate (ATP) hydrolysis to move along the surface of the adjacent microtubule. The ciliary activity is based on the movement of the doublet microtubules in relation to one another, initiated by the dynein arms. Hydrolysis of ATP produces a sliding movement along the microtubule, where the dynein molecules produce a continuous shear force sliding toward the ciliary tip (Fig. ), a movement called the effective stroke. At the same time, a passive elastic connections provided by nexin and the radial spokes accumulate the energy necessary to bring the cilia back to the straight position (recovery stroke).
A plasma membrane surrounds the entire cilia, which is attached to the cell at a structure termed the basal body (also known as a kinetosome). The basal bodies maintain the basic outer ring structure of the cilia, but each of the nine sets of circumferential filaments is composed of three microtubules.
The ciliary motion is often described as whip-like, or compared to the breast stroke in swimming. Adjacent cilia move almost simultaneously (but not quite), so that in groups of cilia, wave-like patterns of motion occur.
Halama et al.
] studied the density and distribution of epithelial cells in the human nasal mucosal using scanning electron microscopy. They showed that the anterior one third of the nasal cavity is non-ciliated but the cilia start occurring just behind the front edge of the inferior turbinate and the posterior part of the nasal cavity as well as the paranasal sinuses are densely covered by cilia. The distribution pattern of ciliated cells corresponds well with a map of nasal airflow indicating that the density of ciliated cells is inversely proportional to the linear velocity of inspiratory air in the nasal cavity (Fig.
). Consequently there are less cilia in the upper part of the nasal cavity than along the floor. Low temperature (in some cases very strong current of cold air with low humidity), low humidity and polluted air may also contribute to a reduced number of ciliated cells in the anterior part of the nasal cavity. However, newborn and laryngoectomized subjects have cilia in the entire nasal cavity [16
]. The current of air contribute highly to the clearance from the nasal cavity and if that current is eliminated e.g. due to obstruction in one site of the nose, the side where normal airflow is obtained show normal distribution of ciliated cells, where the obstructed side show dense cilia.
Sagittal section of the nasal cavity showing the distribution of ciliated, columnar and goblet cells.
Basal cells (Figs. and ) serve as a reserve population by maintaining individual cell replacement in the epithelium. They carry necessary information on each of the other cell types and lie on the basement membrane. These cells do not reach the airway lumen but due to their pluripotency they are able to grow and become the required cell type. Basal cells tend to be prominent because their nuclei form a row in close proximity to the basal membrane.
The anatomy of a basal cell, columnar cell and a goblet cell (left) and a schematic diagram of a microvilli (right).
Columnar Cell, Non-Ciliated
The columnar cells (Fig.
) are like ciliated cells, on the basement membrane and stretch to the airway lumen where they bear microvilli. The microvilli are slender fingerlike cytoplasmic expansions of the cell membrane that have the capability to absorb compounds. It has been shown that a number of drug substances, proteins are absorbed through the columnar cells. The influenza virus also uses this cell type as a port for crossing the nasal mucosal. Due to the microvilli, the surface area of the cell may be increased over 600 times [45
]. The columnar cells contain numerous mitochondria in the apical part, as signs of an active metabolism.
Goblet cells (Fig.
), also called mucus cells or chalice cells, are interspersed among the ciliated and columnar cells throughout the epithelium. They appear to be formed by a modification of the columnar cell. They form granules which consist of mucin or mucigen inside the cell and in the upper part of the cell, while the nucleus is pressed down towards the base [46
]. Like ciliated cells, the distribution of these cells has been mapped where the density of goblet cells is higher in the posterior part of the nose than the anterior [44
]. The average number of goblet cells is about 4.000-7.000 cells per mm2
. These cells are mucin-secreting cells or unicellular glands. Their contribution to the volume of nasal secretions is probably small, compared to submucosal glands, but little is known about their release mechanisms [16
Goblet cells are not under the control of the sympathetic nervous system, like the glands, but respond to irritants, microenviroments or enterotoxins e.g. from Escherichia coli or Vibrio cholerae as well as other factors. The number of goblet cells increases during chronic irritation of the nasal passage. About two-third of the apical part of these cells, is filled with membrane-bound mucin secretory granules that have accumulated there. Once secreted the mucous forms a luminal lining lying on top of the glycocalyx of the microvilli. The mucous lubricates the mucosal surface and forms a barrier which protects the mucosal epithelium from potentially noxious intraluminal substances.
The olfactory cells (Fig.
) are bipolar neurons located in the olfactory region of the nose and the vomeronasal organ. The olfactory epithelium is pseudostratified columnar epithelium with basement membrane like the respiratory epithelium. The epithelium is about 60 µm in height and has a slight yellow-brownish color due to the supporting cells also called the sustentaculum cells [48
]. The olfactory cells are transducers of chemical sensations into neural signals. The mechanism of smell is still not fully understood, but it is known that the plasma membrane of the olfactory cells act as the actual site of chemoreception. Olfactory cells are so specialized that they need a set of supporting cells (Fig.
) to tend to their needs and protect them, these cells are actually sealed to the apex of the olfactory cells. The main body of the olfactory cell is therefore well isolated from the surroundings. To the apical surface stretched a dendrite, about 1 µm thick and the part expressed on the surface is called dendrite or olfactory knop, wherefrom about 6-10 cilia may be seen. The olfactory cilia are very long, over 50 µm having same microstructure as the cilia with microtubule. They are covered with mucus and float on the epithelial surface. These cilia are not motile. From the base, the ciliated cell is exposed through the axon (about 0,2 µm thick). Numerous axons are then bundled together to form so-called filia olfactoria, which may be seen going in the cribriform plate into the olfactory lobe of the brain. As shown in (Fig.
) there are numerous axons from other olfactory cells that go through each foramina and give rise to the olfactory nerve. Various studies have shown that absorption may also occur through the olfactory region. In many animals, however, such as the rabbit and the dog, this region will not be easily exposed by the drug.
The structure of an olfactory cell together with supporting cells and basal cells (left) and olfactory mucosa (right).
The olfactory cells require supporting cells called sustentaculum cells (Fig. ). They are the most numerous cells in the olfactory epithelium and they provide metabolic and physical support to the olfactory cells as well as protection. They are known to possess lipofuscin granules. As mentioned above, the olfactory cells are sealed to these supporting cells, but not with gap and tight junctions. They are similar to the columnar cells, with numerous microvilli, but abundant of mitochondria. The nuclei of these cells are usually located more apically than other epithelial cells.
The olfactory epithelium as well as the vomeronasal organ present a small number of brush cells. They have large microvilli at their apical surface, but the basal surface is in synaptic contact with nerve fibers that penetrate the basal membrane. These nerve fibers are terminal branches of the trigeminal nerve (fifth cranial nerve), that has a more sensation function than olfaction [49
]. Their function is receptor cells of general sensation such as irritation or other form of sensory stimulation of the mucosa.