**1. Introduction**

The novel Coronavirus disease of 2019 (covid-19) caused by the Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 was first reported in Wuhan, China in December 2019 and had continued to ravage the world, causing widespread respiratory health problems and mortalities. The virus targets mainly the

respiratory tract. It enters the lungs through the upper respiratory tract and attacks alveoli epithelial type2 (AT2) cells [1]. Many patients succumb to pneumonia in severe SARS-CoV-2 infections.

In the advent of the covid-19 pandemic, there had been a renewed focus on the mammalian respiratory anatomy and physiology. In this regard, this calls for a broader perspective and understanding of the anatomy and physiology of the respiratory system. This chapter therefore provides an overview of the functional anatomy and immunology of the respiratory tract in the context of the covid-19 pandemic.

### **2. Anatomical organization of the respiratory tract**

The mammalian respiratory system consists of tissues and organs whose main function is to ensure exchange of oxygen and carbon dioxide between the organism and the external environment. From the functional perspective, the respiratory system is viewed as consisting of a conducting part and a gaseous exchange part while from a purely anatomical perspective the respiratory system is viewed as being composed of an upper respiratory component and a lower respiratory component.

The conducting part of the respiratory system, also known as the conducting airways, is that part of the respiratory system that merely transports gases from the external environment to the lungs and from the lungs to the external environment, while the gaseous exchange part is that part of the respiratory system that is responsible for the diffusion of gases (particularly oxygen and carbon dioxide) into and out of the blood capillaries of the lungs. Structures from the nasal cavity up to the terminal bronchioles constitute the conducting part of the respiratory tract. The conducting part also serves a protective function by conditioning the air that has been inhaled [2]. Conditioning of the inspired air by the conducting airways includes heating the air to body temperature, filtering out harmful gases and particles such as dust and bacteria as well as saturating the air to 100% relative humidity [2]. In trapping and filtering out harmful gases and particles, the respiratory tract uses a mucociliary escalator or mucociliary blanket. The mucociliary escalator is composed of cilia, mucus and a layer of fluid known as the periciliary layer. The fluid on the surface of the airways is constantly propelled by cilia from near the lungs to regions far away from the lungs towards the nasal cavity to be expelled.

The conducting part terminates at the terminal bronchioles before transforming into the gaseous exchange zone. The gaseous exchange zone is located within the lung parenchyma. The components of the gaseous exchange zone consist of the respiratory bronchioles, alveolar ducts and alveolar sacs together with their alveoli [2]. The gaseous exchange zone is a thin membrane that exists between the alveoli space and the pulmonary capillary blood. The pulmonary capillary blood network thoroughly covers the alveoli walls and receives the major cardiac output of the right ventricle via the pulmonary trunk [2–3].

The entire mammalian respiratory tract from the nasal cavity to the bronchi tree is lined by a mucus membrane known as the respiratory mucosa. The respiratory mucosa consists of epithelial cells that sit on top of a layer of loose connective tissue. The main function of the respiratory mucosa is to prevent pathogens and noxious particles from reaching the lungs. In most parts of the respiratory tract, the respiratory mucosa secretes a thick protective mucus layer. Generally, the respiratory mucosa consists of a pseudostratified columnar epithelium and an underlying loose connective tissue known as the lamina propria. The epithelium normally transitions in structure from the nasal cavity towards the lungs starting with a pseudostratified columnar epithelium in the nasal cavity and ending with a simple squamous or

*Refocusing Functional Anatomy and Immunology of the Respiratory Mucosa in the Advent… DOI: http://dx.doi.org/10.5772/intechopen.96251*

cuboidal epithelium in the alveoli. The respiratory mucosa contains different types of epithelial cells that range from ciliated columnar to simple squamous. Within the respiratory tract epithelial cells are found mucus-secreting cells such as goblet cells and some specialized glands containing both mucus and serous cells [4].

Throughout the respiratory tract from the nasal cavity to the alveoli, sheets of cells cover the internal surface. The sheets of cells, known as epithelium, differ in structure and function depending on the location within the respiratory tract. The major part of the respiratory tract, from the nasal cavity to the bronchi, is lined by a pseudostratified columnar epithelium. From the bronchi downwards to the bronchioles, the epithelium changes into a simple columnar to cuboidal epithelium. The epithelium then changes in the alveoli to become a thin squamous epithelium that allows for gaseous exchange to take place. The epithelial cells sit on top of a basement membrane below which lies a layer of loose connective tissue known as the lamina propria [4].

Anatomically, the respiratory tract is viewed as consisting of the upper and lower parts. The upper respiratory tract consists of the nasal cavity and adjoining paranasal sinuses, pharynx and the portion of larynx above the vocal folds. The lower respiratory tract comprises of the lower parts of the larynx, the trachea, bronchi, bronchioles and the alveoli [5].

#### **3. The upper respiratory tract**

The upper respiratory tract is composed of the nose and nasal cavity, the pharynx and the larynx. It is the first entry point for air and other potentially harmful substances including bacteria and viruses. The upper respiratory tract functions in the filtration, warming and humidification of the inspired air. In addition, the upper respiratory tract contains nerve endings of the first cranial nerve known as the olfactory nerve which is responsible for detecting odors in the inspired air. This section provides an account of the functional anatomy of the major components of the upper respiratory tract particularly the nasal cavity and pharynx.

#### **3.1 The nasal cavity**

Up to 90% or more of inspiration occurs through the nose and therefore the nasal cavity is an important site for initial infection by most microorganisms including SARS-CoV-2. Moreover, SARS-CoV-2 infection via the ocular route is hypothesized to occur via drainage of virus-laden tears into the nasal cavity through the nasal lacrimal duct [6–8].

The air entering the respiratory tract is usually dry, cold and containing potentially harmful particulate matter. Therefore, the major function of the nasal cavity is to humidify and warm the inspired air. As the air passes through the nasal cavity, airborne particles are filtered off including microorganisms before the air reaches the lower respiratory tract. In addition, the nasal cavity is an olfactory (smell) organ and also helps in draining and clearing the paranasal sinuses and lacrimal ducts [7].

Entrance into the nasal cavity is provided by the nostrils, which are two external openings into the nasal cavity. The nasal cavity consists of the nasal skeleton which is made up of a combination of parts of bones such as the maxilla, the ethmoid, the perpendicular part of the palatine bone and the medial pterygoid plate. The nasal cavity is divided into two separate cavities by a cartilaginous nasal septum. Each half of the nasal cavity consists of a roof, floor, medial wall and lateral wall. The nasal septum is made up of cartilage and bone. In contrast to the lateral walls, the floor and the roof of the nasal cavity which are covered by a pseudostratified

columnar epithelium, the nasal septum is covered by squamous epithelium [9]. The posterior boundary of the nasal cavity is provided by the choanae also known as posterior nasal apertures. The choanae open into the nasopharynx [10–12].

Four paranasal sinuses surround the nasal cavity in humans. These are the frontal sinuses (superior anterior), ethmoid sinuses (superior), paired maxillary sinuses (lateral), and sphenoid sinuses (posterior). The paranasal sinuses communicate with the nasal cavity through ducts that drain through ostia, which empty into spaces located on the lateral wall. Only the sphenoid paranasal sinus empties into the posterior roof of the nasal cavity [13].

There are three recognizable regions within each half of the nasal cavity: the nasal vestibule, respiratory region and olfactory region.

#### *3.1.1 Nasal vestibule*

The first part of the nasal cavity immediately posterior to the nostrils is the nasal vestibule. The initial half of the nasal vestibule is covered by a keratinized stratified squamous epithelium that contains hairs known as vibrissae. The function of the vibrissae is to filter inhaled particles. The second half of the nasal vestibule is covered by a pseudostratified ciliated columnar epithelium [14, 15].

#### *3.1.2 Respiratory region*

The respiratory region is the main part of the nasal cavity and is that part which houses the nasal conchae (or turbinate bones) and meatuses. Nasal conchae are curved shelves of bone that protrude from the lateral walls of the nasal cavity. The spaces between the nasal conchae are referred to as meatuses. The main functions of the respiratory region are to humidify and warm the inspired air and to trap and eliminate particulate matter. The respiratory region is covered in respiratory epithelium (pseudostratified ciliated columnar epithelium) and mucous cells.

As the air passes through the nasal cavity, it is warmed to body temperature and is humidified to near 100%. The warming and humidification of the inspired air is aided by the neuromuscular network within this region. The neuromuscular network of the respiratory region regulates airflow within the nasal cavity by controlling the blood volume in the erectile tissue on the turbinate bones. Under normal physiological conditions, the erectile tissue is continuously stimulated by the sympathetic nervous system to prevent nasal congestion [13].

Airborne particles that escape trapping in the nasal vestibule become trapped in the mucous produced by the respiratory nasal mucosa. The trapped particles are then eliminated by the ciliated cells of the mucociliary system which sweep mucous and trapped particles at a rate of 1 cm per minute into the naso-pharynx for further expulsion [16].

#### *3.1.3 Olfactory region*

One of the most commonly reported neurological indicators of SARS-CoV-2 infection is the temporary loss of smell (anosmia). Studies suggest that anosmia better predicts SARS-CoV-2 infection than other well-known symptoms such as fever and cough. Furthermore, studies suggest that the novel coronavirus changes the sense of smell in patients not by directly affecting neurons but by affecting the function of sustentacular or supporting cells [17, 18].

The olfactory region is a small area located at the superior apex of the nasal cavity and the ethmoturbinates and is lined with olfactory receptor cells. The olfactory *Refocusing Functional Anatomy and Immunology of the Respiratory Mucosa in the Advent… DOI: http://dx.doi.org/10.5772/intechopen.96251*

region is responsible for sensing odors in inspired air. It is lined by an olfactory epithelium which is made up of a pseudostratified epithelium that contains olfactory sensory receptor cells, supporting cells and mucus secreting glands. The olfactory receptor neuron is a bipolar cell that gives rise to a small-diameter, unmyelinated axon at its basal surface that transmits olfactory information centrally. At its apical surface, the receptor neuron gives rise to a single process that expands into a knoblike protrusion from which several microvilli, called olfactory cilia, extend into a thick layer of mucus [19]. The fibers of the olfactory sensory receptor cells have their axonal projections onto the olfactory bulb of the brain [20, 21]. For efficient detection of odors in the inspired air, afferent (in-coming) airflow needs to be directed orthonasally (straight) and retronasally (backwards) in order for the nasal olfactory epithelium to pick up the odor [13]. The odor particles become trapped in the mucous and bind to odorant-binding proteins that concentrate and help to solubilize the odor particles. The odor particles then get attached to olfactory receptors located on the cilia of olfactory cells. Upon stimulation of the odor receptors, the odor signals are transmitted up through the cribriform plate to synapse with neurons of the olfactory bulb which then send the signals through the olfactory nerve (CNI) into the secondary neurons for higher processing. A unique feature of the olfactory receptors is that a single receptor cell can detect only one odorant type [13, 20, 22, 23].

#### *3.1.4 Nasal conchae (turbinate bones) and meatuses*

Nasal conchae, also known as turbinate bones, are any of several thin, scrollshaped bony elements originating from the lateral walls of the nasal cavity. Each half of the nasal cavity has three turbinate bones named superior, middle and inferior turbinates. The superior and middle turbinates extend from the ethmoid bone. The inferior turbinate bone is independent of the superior and middle turbinates. The inferior turbinate is the most anteriorly located and therefore the first of the turbinate bones to come into contact with inspired air. The turbinate bones, particularly the anteriorly located inferior turbinate, are involved in innate and adaptive immune reactions of the nasal cavity [14].

Nasal meatuses are spaces found between the turbinate bones and the nasal cavity walls. There are four meatuses in the nasal cavity: the superior meatus, the middle meatus and the inferior meatus.

*Superior meatus.* The superior meatus is located inferior to the superior turbinate and superior to the middle turbinate bones; this is the drainage site of the posterior ethmoid sinus.

*Middle meatus.* The middle meatus is located inferior to the middle turbinate and superior to the inferior turbinate. This is the drainage site of the frontal, anterior ethmoid, and maxillary sinuses.

*Inferior meatus.* The inferior meatus is located inferior to the inferior turbinate and superior to the floor of the nasal cavity. The nasolacrimal duct drains tears from the lacrimal sac at the medial canthus of the eye into the anterior portion of this meatus via Hasner's valve [13].

#### *3.1.5 Blood supply and lymphatics of the nasal cavity*

The nasal cavity has a rich vascular supply which allows it to effectively regulate humidity and temperature of the inhaled air. The nasal cavity is also supplied by a network of lymphatic vessels which drain into various lymph nodes located in the pharyngeal region and the neck.

#### *3.1.5.1. Blood supply*

The function of warming and humidifying the inspired air in the nasal cavity is achieved by an elaborate network of blood vessels. The mucosa of the nasal cavity enlarges and shrinks due to sympathetic innervation of the nasal vasculature.

The main sources of arterial blood to the nasal cavity are the internal and external carotid arteries [24]. The internal carotid artery gives off the ophthalmic artery which in turn gives off two main branches to the nasal septum: the anterior and posterior ethmoidal arteries and the dorsal nasal artery. The anterior ethmoid artery supplies the lateral nasal wall and the nasal septum. The posterior ethmoid artery supplies the superior turbinate and the nasal septum [9, 14].

The external carotid artery gives off the maxillary artery and facial artery. The maxillary artery gives off a smaller artery known as the descending palatine artery which then passes through the pterygopalatine fossa through the palatine canal before it branches into the greater and lesser palatine arteries. The greater palatine artery enters the greater palatine foramen on the posterior aspect of the palate before traversing the palate anteriorly to enter the nasal cavity via the incisive canal. The greater palatine artery supplies the septum and the floor of the nasal cavity. The sphenopalatine artery, a branch of the maxillary artery, supplies the middle and inferior turbinate bones as well as the posterior part of the nasal septum [25].

The facial artery, a branch of the external carotid artery, gives rise to three arteries namely, the superior labial artery, the lateral nasal artery and the angular artery. The three arteries supply the nasal septum, nasal vestibule and dorsal nasal cavity respectively [25].

A common site of epistaxis (nose bleeding) in the nasal cavity commonly occurs at Kiesselbach's plexus (Little's area) located in the anterior nasal septum. This plexus is a vascular anastomosis between the anterior ethmoid artery, superior labial artery, greater palatine artery and the terminal branch of the posterior septal branch of the sphenopalatine artery [26]. The names of the veins that drain the nasal cavity follow those of the arteries with which they pair.

#### *3.1.5.2. Lymphatic drainage of the nasal cavity*

In general, the main functions of the lymphatic system in the nasal cavity include transportation of old leukocytes from the lymph nodes in the vicinity of the nasal cavity to the blood and transportation of antigen-presenting cells (APCs) to the lymph nodes in order to trigger an immune response.

Lymph from the vestibule of the nasal cavity is drained into the submandibular lymph nodes. The anterior one third of the nasal cavity is drained by lymphatic vessels that deposit their lymph fluid in the submaxillary lymph nodes. The posterior two thirds of the nasal cavity including the ethmoid sinuses is drained by lymphatic vessels that deposit lymph partly into the retropharyngeal lymph nodes and partly into the superior deep cervical lymph nodes [27].

#### *3.1.6 Nerves of the nasal cavity*

The first cranial nerve (olfactory-CNI) transmits signals from the nasal cavity to the brain to provide the sense of smell. The olfactory epithelium is in the superior portion of the nasal cavity. Within this epithelium are sensory cilia that project up through the cribriform plate to the olfactory bulb. From the olfactory bulb, signals are sent through the olfactory nerve proper to a network of secondary neurons for processing before ending up in the brain [28].

*Refocusing Functional Anatomy and Immunology of the Respiratory Mucosa in the Advent… DOI: http://dx.doi.org/10.5772/intechopen.96251*

Sensory innervation to the external and internal parts of the nasal cavity is provided by the trigeminal nerve through its two branches the ophthalmic nerve and maxillary nerve [29].

#### *3.1.7 Paranasal sinuses*

The nasal cavity is extended by the paranasal sinuses. These are air-filled cavities found in some bones surrounding the nasal cavity. In the human, there are four pairs of paranasal sinuses which are named based on the bones in which they are found. The four sinuses are: the maxillary, frontal, sphenoid, and the ethmoid. The inner surfaces of the four paranasal sinuses are lined by a ciliated pseudostratified epithelium containing mucus-secreting goblet cells. Paranasal sinuses may serve in lightening the weight of the head, humidifying and warming of inspired air, increasing the resonance of speech, providing mechanical rigidity and increasing olfactory surface area [10].
