**4. The lower respiratory tract**

All the structures from the trachea down to the alveoli constitute components of the lower respiratory tract. The components of the lower respiratory tract with support from the rib cage and diaphragm pull in the inspired air from the upper respiratory tract and transport it to the alveoli where oxygen is absorbed into the blood stream and carbon dioxide is released in exchange.

## **5. Functional anatomy of the lower respiratory tract mucosa**

The mucosa of the respiratory tract is lined by a pseudostratified columnar epithelium which consists of a variety of cells (**Figure 1**). It has been estimated

#### **Figure 1.**

*Schematic diagram showing apical junctional complexes found in the respiratory airway epithelium. Shown in this diagram are tight junctions (black) and adherens (blue). Apical junctional complexes are a key component of the innate immune system in the respiratory tract that form between two neighboring cells. Apical junctional complexes consist of mainly tight junctions and adherens junctions. Tight junctions control intercellular movements of ions and other molecules while adherens junctions are responsible for the initiation and maintenance of cell-cell adhesion.*

**Figure 2.**

*Schematic diagram showing the components of the mucociliary clearance system. The mucus layer traps particles suspended in the inhaled air. The trapped particles are then propelled by cilia with the aid of the serous layer towards pharynx.*

that the total number of cells covering the lower human respiratory tract is 1010 cells that covers a surface area of 2,500cm3 [30]. The pseudostratified columnar epithelium consists of four major cell types which lie on a continuous basement membrane. The four major cell types of the pseudostratified columnar epithelium are the ciliated, secretory, undifferentiated intermediate and basal cells (**Figure 1**). The function of the basal and the undifferentiated intermediate cells is to act as the progenitors of the other respiratory epithelium cells. The ciliated columnar cell type is the most predominant cell of the respiratory epithelium. It rests on a basement membrane and tapers towards the surface. On its luminal surface, the ciliated cells bear numerous cilia which distinguish them from other cell types. Cilia are hair-like cellular organelles that project from the surface of the cell [31, 32]. The luminal surface of each ciliated cell contains about 200–300 cilia. Each of the cilia on the luminal surface of the upper airways is estimated to be about 0.25 μm in diameter with a height of about 6.5 μm. The dimensions are smaller in the lower respiratory tract. In addition, there are numerous microvilli on the apical surface of the ciliated cells. The role of the microvilli is to ensure trans-epithelial movement of fluids and electrolytes. Ciliated cells are interconnected by tight junctions (**Figure 2**). These tight junctions are specialized protein structures that are responsible for regulating the passage of solutes and ions across the epithelial barrier [30, 33]. Thus, the tight junctions act as sieves that only allow the passage of selected substances.

#### **6. Immune mechanisms of the respiratory tract**

Respiratory infections are among the top 5 causes of high morbidity and mortality globally. Respiratory infections pose a continuous threat to humans due to their easy dissemination via aerial transmission as evidenced recently by the covid-19 pandemic [34].

A number of factors play different roles in the defense mechanism of the respiratory tract. The defense mechanism of the respiratory tract exists within two broad categories i.e. the humoral immunity and cell-mediated immunity components. In addition, the physical or innate immune defense mechanism plays a critical role as the first line defense mechanism within the respiratory tract. The innate defense

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

mechanism of the respiratory tract consists of non-specific physical barriers that can prevent noxious substances from accessing the delicate part of the respiratory system such as the alveoli thereby averting injury to those components.

The respiratory immune response consists of multiple tiers of cellular responses that are engaged in a sequential manner in order to control infections. In addition, specific mechanisms are in place to promote disease tolerance in response to respiratory infections. Various physical barriers, cell types and chemicals are involved in the respiratory system immune response and coordinate pathogen clearance and tissue repair within the respiratory tract [35]. The immune response within the respiratory tract follows an ordered, stepwise program of engagement of distinct tiers of defense [36].

Local sensor cells first detect the invading microorganism. This detection event can trigger cell-intrinsic defense responses that contain the pathogen, lead to secretion of chemo-attractants to recruit rapid responder cells such as neutrophils, and alert lung-resident lymphoid cells through the secretion of first order cytokines. The complex interplay between resident and infiltrating immune cells and secreted innate immune proteins shapes the outcome of host-pathogen, host-allergen, and host-particle interaction within the mucosal airway compartment [37].

#### **6.1 Airway barrier defenses**

The first line of defense against infection in the respiratory tract is the mucosal epithelium. The pulmonary epithelium initially acts as a physical barrier between the airway lumen and the vasculature. The epithelium provides the physical barrier by the formation of tight junctions that include claudins, occludins, and adherens.

The physical and chemical barrier to the airways is provided by four major cell types. These cells include ciliated cells, mucus-secreting goblet cells, and club cells, which produce antimicrobial compounds. Basal cells, along with club cells serve as regional progenitor cells to replenish the other cell types [38]. The proportion of each cell type, and the associated defense mechanisms, are compatible with the airway diameter. In the human respiratory tree, ciliated cells and mucus-secreting cells create the barrier defense in larger airways, whereas mucus-secreting cells become less frequent and secretory cells become more predominant in smaller airways. Within the alveoli, alveolar type 1 cells facilitate gas exchange whereas alveolar type 2 cells secrete pulmonary surfactant [35].

#### **6.2 The mucociliary system as a respiratory tract defense barrier**

Arguably, the most important component of the innate immune mechanism of the respiratory tract is the mucociliary systems. The mucociliary system is one of the primary mechanisms for protecting the respiratory tract tissues. It operates through the coordinated functions of mucus and cilia that trap and eliminate inhaled materials. Mucociliary action also ensures elimination of dead endogenous cells and debris [39].

The mucociliary clearance system (**Figure 2**) refers to the composite structures within the respiratory tract that are responsible for eliminating mucus and potentially harmful foreign materials from the respiratory tract. It is a selfcleansing mechanism of the respiratory tract and forms the major first line defense mechanism of the lungs [16]. The main components of the mucociliary clearance apparatus are the cilia found on columnar ciliated cells and the mucus produced by mucus secretory cells known as goblet cells. A layer of fluid and mucus known as the airway surface or periciliary layer covers the airways and this layer of fluid and mucus is constantly propelled by cilia from the distal to the proximal lungs [16].

The mucociliary clearance is a component of the innate immune defense mechanism [40]. In order for the lungs to perform normally, a properly functioning mucociliary escalator is cardinal. Problems with components of the mucociliary escalator, either the mucus or cilia, may cause airway blockage which may result in accumulation of harmful germs and particulate matter, thereby causing damage to the lungs [36]. High morbidity and mortality in many respiratory diseases have been attributed to dysfunctions in components of the mucociliary escalator including abnormal biophysical properties of mucus and ciliopathy [41]. Furthermore, some studies had shown that the majority of the pre-existing conditions that increased the risk of death from COVID-19 are the same diseases that were affected by long-term exposure to air pollution particularly exposure to fine particulate matter [42]. This may indicate that damage to the mucociliary escalator may be responsible for the high risk to covid-19 infection and other respiratory infections among people chronically exposed to air pollution. Treatment to reduce abnormalities of components of the mucociliary escalator have been shown to improve outcomes in respiratory diseases indicating the importance of the mucociliary escalator in pulmonary defense.
