Nonphysiological Functions of the Lung : Host Defense and Metabolism

Periciliary Fluid Layer

The periciliary fluid layer is composed of nonviscous serous fluid, which is produced by the pseudostratified ciliated columnar epithelial cells that line the airways. These cells have the ability to either secrete fluid, a process that is mediated by activation of cystic fibrosis transmembrane regulator (CFTR) chloride (Cl ⁻ ) ion channels ( Na ⁺ secretion follows passively between cells across the tight junctions) or reabsorb fluid, a process that is mediated by activation of epithelial sodium channels (ENaC; Cl ⁻ absorption follows passively between cells across the tight junctions). NaCl secretion or reabsorption temporarily establishes an osmotic gradient across the pseudostratified epithelium, which provides the driving force for passive water movement. The balance between CFTR-mediated Cl ⁻ secretion and ENaC-mediated Na ⁺ absorption is regulated by a variety of hormones and determines the volume of the periciliary fluid, which in the healthy lung is 5 to 6 µm deep, a level that is optimal for rhythmic beating of the cilia and mucociliary clearance.

In the Clinic

Cystic fibrosis (CF) is the most common lethal inherited disease among white people. It is an autosomal recessive disease caused by mutations in the CFTR gene. It is characterized by chronic bacterial lung infection, progressive decline in lung function, and premature death at an average age of 38 years. More than 1000 mutations of the CFTR gene have been described, but 70% of affected individuals have a deletion of phenylalanine at codon 508 (ΔF508-CFTR) in at least one allele. This mutation results in a lack of Cl ⁻ secretion and an increase in ENaC-mediated Na ⁺ reabsorption, which in turn results in a reduction in the volume of the periciliary fluid.

Detailed study of the different CFTR mutations has resulted in an understanding of various disease-related phenotypes, some of which are associated with milder disease and some with more severe disease. Since the 1980s, research findings have elucidated how many of the most common mutations in the CFTR gene cause CF, and this has led to the development of drugs that target specific mutations and reverse the progressive reduction in lung function. For example, in one mutation (G551D-CFTR, which affects ≈5% of patients with CF), the CFTR Cl ⁻ channel reaches the plasma membrane of airway epithelial cells but does not secrete Cl ⁻ . Through precision medicine, a drug, ivacaftor (Kalydeco), has been found to stimulate Cl ⁻ secretion via the G551D-CFTR, thereby improving lung function and decreasing the rate of disease progression. When the alleles are homozygous for the ΔF508-CFTR mutation (which affects ≈50% of patients with CF), the CFTR Cl ⁻ channel does not reach the plasma membrane of airway epithelial cells.

In 2015, the U.S. Food and Drug Administration approved a combination drug therapy, lumacaftor/ivacaftor (Orkambi), that has been shown to correct the gene defect, increase the amount of ΔF508-CFTR in the plasma membrane, and improve Cl ⁻ transport. Clinically, both ivacaftor and lumacaftor/ivacaftor have been shown to improve lung function significantly and to decrease the rate of decline in lung function.

Mucus Layer

The mucus layer lies on top of the periciliary fluid layer and is composed of a complex mixture of macromolecules and electrolytes. Because the mucus layer is in direct contact with air, it entraps inhaled substances, including pathogens. The mucus layer is predominantly water (95% to 97%), 5 to 10 µm thick and exists as a discontinuous blanket (i.e., islands of mucus). Mucus has low viscosity and high elasticity and is composed of glycoproteins with groups of oligosaccharides attached to a protein backbone. Healthy individuals produce approximately 100 mL of mucus each day. Four cell types contribute to the quantity and composition of the mucus layer: goblet cells and Clara cells within the tracheobronchial epithelium, and mucous cells and serous cells within the tracheobronchial submucosal glands. Goblet cells, also referred to as surface secretory cells, represent approximately 15% to 20% of the tracheobronchial epithelium, and are found in the tracheobronchial tree up to the 12th division. In many respiratory diseases, goblet cells appear further down the tracheobronchial tree; thus the smaller airways are more susceptible to obstruction by mucus plugging. Goblet cells secrete neutral and acidic glycoproteins rich in sialic acid in response to chemical stimuli. In the presence of infection or cigarette smoke or in patients with chronic bronchitis, goblet cells can increase in size and number, extend above the 12th division of the tracheobronchial tree, and secrete copious amounts of mucus. Injury and infection increase the viscosity of the mucus secreted by goblet cells, which reduces mucociliary clearance of inhaled particles and pathogens.

Submucosal tracheobronchial glands are present wherever there is cartilage in the upper regions of the conducting airways, and they secrete water, ions, and mucus into the airway lumen through a ciliated duct (see Fig. 26.1 ). Although both mucous and serous cells secret mucus, their cellular structure and mucus composition are distinctly different ( Table 26.1 ). In several lung diseases, including chronic bronchitis, the number and size of submucosal glands are increased, which leads to increases in mucus production, alterations in chemical composition of mucus (i.e., increased viscosity and decreased elasticity), and the formation of mucus plugs that cause airway obstruction. Mucus secretion from submucosal tracheobronchial glands is stimulated by parasympathetic (cholinergic) compounds such as acetylcholine and substance P and inhibited by sympathetic (adrenergic) compounds such as norepinephrine and vasoactive intestinal polypeptide. Local inflammatory mediators such as histamine and arachidonic acid metabolites also stimulate mucus production.

Clara cells, located in the epithelium of bronchioles, also contribute to the composition of mucus through secretion of a nonmucinous material containing carbohydrates and proteins. These cells play a role in bronchial regeneration after injury.

At the Cellular Level

Sputum is expectorated mucus. However, in addition to mucus, sputum contains serum proteins, lipids, electrolytes, Ca ⁺⁺ , DNA from degenerated white blood cells (collectively known as bronchial secretions ), and extrabronchial secretions; including nasal, oral, lingual, pharyngeal, and salivary secretions. The color of sputum is more closely correlated with the amount of time that it has been present in the lower respiratory tract than with the presence of infection. Although not precisely identifiable with disease diagnosis, the color of sputum can be informative in helping lead to a diagnosis and stage of disease. Mucus has many colors: white, yellow, green, red, pink, brown, gray, and black. The coloration is commonly due to the type of cell present in the airways (inflammatory cells, such as neutrophils or eosinophils, or red blood cells) and how long they have been there. Clear or cloudy white thin mucus is considered normal; however, if amounts and thickness are increased, it may represent an early sign of infection. Thick white mucus can be the only identifiable feature of gastroesophageal reflux disease caused by gastric acid reflux into the airways. Yellow and green coloration of mucus is due to the presence and breakdown of neutrophils and eosinophils in infectious and allergic diseases. Yellow is typically associated with more acute disease (infection, allergy) and green usually indicates a more chronic stage with the presence of bacteria (chronic bronchitis, bronchiectasis, cystic fibrosis, and lung abscess). Red mucus indicates the presence of red blood cells in the airways and is associated with pneumococcal pneumonia, lung cancer, tuberculosis, and pulmonary emboli. Pink mucus is typically associated with the breakdown of eosinophils in individuals with allergies. Gray, brown, and black mucus is often associated with cigarette or marijuana smoking, cocaine use, air pollution (workplace environment, such as coal mines), and old blood.

Ciliated Cells and Cilia

As noted previously, the respiratory tract to the level of the bronchioles is lined by a pseudostratified, ciliated columnar epithelium (see Fig. 26.1 ). These cells maintain the level of the periciliary fluid in which cilia and the mucociliary transport system function. Mucus and inhaled particles are removed from the airways by the rhythmic beating of the cilia. There are approximately 250 cilia per airway epithelial cell, and each is 2 to 5 µm in length. Cilia are composed of nine microtubular doublets that surround two central microtubules held together by dynein arms, nexin links, and spokes. The central microtubule doublet contains an adenosine triposphatase (ATPase) that is responsible for the contractile beat of the cilium. Cilia beat with a coordinated oscillation in a characteristic, biphasic, and wave-like rhythm called metachronism. They beat at approximately 1000 strokes per minute, with a power forward stroke and a slow return or recovery stroke. During their power forward stroke, the tips of the cilia extend upward into the viscous mucus layer and thereby move it and the entrapped particles. On the reverse beat, the cilia release the mucus and withdraw completely into the sol layer. Cilia in the nasopharynx beat in the direction that propels the mucus into the pharynx, whereas cilia in the trachea propel mucus upward toward the pharynx, where it is swallowed.