Epithelium

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Upper airways

The nasal cavity, the nasopharynx, larynx, trachea and bronchi are lined with pseudostratified, ciliated, columnar epithelium with many goblet cells. There are also coarse hairs in the nasal region of the respiratory tract.

Bronchi and bronchioles

The bronchi, but not the bronchioles, have mucous and serous glands present. The bronchioles, however, possess goblet cells and the wall contains a well-developed layer of smooth muscle cells, capable of narrowing the airway. The epithelium in the terminal and respiratory bronchioles consists largely of ciliated, cuboidal cells and smaller numbers of Clara cells. The ciliated epithelial cells each have about 20 cilia with an average length of 6 pm and a diameter of 0.3 pm Each cilium is composed of a central doublet and 9 peripheral filaments which function as a structural support. Contractions result in successive beats of the cilia creating a wave which consists of a fast propulsion stroke followed by a slow recovery stroke. Clara cells become the most predominant type in the most distal part of the respiratory bronchioles. They have ultrastructural features of secretory cells but the nature and function of the secretory product is poorly understood.

Alveoli

In the alveolar ducts and alveoli the epithelium is flatter and becomes the simple, squamous type, 0.1 to 0.5 pm thick. The alveoli are packed tightly and do not have separate walls, adjacent alveoli being separated by a common alveolar septum with communication between alveoli via alveolar pores (Figure 10.4). The alveoli form a honeycomb of cells around the spiral, cylindrical surface of the alveolar duct. The exposed alveolar surface is normally covered with a surface film of lipoprotein material.

Capillai

Capillai

v Perivascular Interstitial Space

Figure 10.4 Cross-section of the alveoli v Perivascular Interstitial Space

Figure 10.4 Cross-section of the alveoli

There are several types of pulmonary alveolar cells. Type I (or small type A), are non-phagocytic, membranous pneumocytes. These surface-lining epithelial cells are approximately 5 pm in thickness and possess thin squamous cytoplasmic extensions that originate from a central nucleated portion. These portions do not have any organelles and hence they are metabolically dependent on the central portion of the cell. This reduces their ability to repair themselves if damaged.

Attached to the basement membrane are the larger alveolar cells (Type II, type B or septal cells). These rounded, granular, epithelial pneumocytes are approximately 10 to 15 pm thick. There are 6 to 7 cells per alveolus and these cells possess great metabolic activity. They are believed to produce the surfactant material that lines the lung and to be essential for alveolar repair after damage from viruses or chemical agents.

Alveolar-capillary membrane

The blood and alveolar gases are separated by the alveolar capillary membrane (Figure 10.4) which is composed of a continuous epithelium of 0.1 to 0.5 pm thickness, a collagen fibre network, a ground substance, a basement membrane and the capillary endothelium. The interstitium is composed of the basement membrane of the endothelium, a ground substance, and epithelium. It forms a three dimensional skeleton to which the alveoli and capillaries are attached. Maximum absorption probably occurs in the areas where the interstitium is the thinnest (80 nm) since the surfactant is also thin in these areas (15 nm). Drainage of the interstitial fluid occurs by passage into the lymphatics, which often happens long after passage along the alveolar wall.

The thickness of the air-blood barrier varies from 0.2 pm to 10 pm. The barrier is minimal when the thickness is less than 0.5 pm since the epithelium and endothelium are present only as thin cytoplasmic extensions and the interstitium exists as a narrow gap between mostly fused membranes. When the diameter exceeds 0.5 pm additional structural elements are present. The minimal barrier thickness is nearly identical in structure and dimensions in all mammalian species that have been investigated. This is in contrast to the alveolar surface areas which increase proportionally with body weight.

Lung permeability

The alveolar epithelium and the capillary endothelium have a very high permeability to water, most gases and lipophilic substances. There is an effective barrier however for many hydrophilic substances of large molecular size and for ionic species. The alveolar type 1 cells have tight junctions, effectively limiting the penetration of molecules to those with a radius of less than 0.6 nm. Endothelial junctions are much larger, with gaps of the order of 4 to 6 nm. Clearance from the alveoli by passage across the epithelium bears an approximate inverse relationship to the molecular weight. The normal alveolar epithelium is almost totally impermeable to proteins and small solutes, for example the half-time for turnover of albumin between plasma and the alveolar compartment is of the order of 36 hours1. The microvascular endothelium, with its larger intercellular gaps, is far more permeable for all molecular sizes and there is normally an appreciable leak of protein into the systemic circulation.

Lung mucus

A thin fluid layer called the mucous blanket, 5 pm in depth, covers the walls of the entire respiratory tract (Figure 10.5). This barrier serves to trap foreign particles for subsequent removal and prevents dehydration of the surface epithelium by unsaturated air taken in during inspiration.

There are about 6000 tracheo-bronchial glands in man, with an average of one cell per square millimetre of surface area. The ratio of goblet cells to ciliated cells is 1 to 5 in the large airways and 1 to several hundred in the bronchioles. The mucus largely originates from the vagally innervated, submucosal glands, with a smaller contribution from goblet cells. Within the gland, distal serous cells secrete a watery fluid, whereas the mucus cells near the neck secrete a gel. It is speculated that the secretions of the serous cells help in the movement of the swollen gel to the surface. Although the mucus producing cells are under vagal control and can be regulated by cholinergically mediated drugs, goblet cells discharge mucus without physiological stimulation.

The main component of nasal mucus appears to be a mucopolysaccharide complexed with sialic acid. Mucus contains 2-3% mucin, 1-2% electrolytes, and the remainder water. Tracheo-bronchial mucus has viscoelastic properties and it averages 5% solids, including

Basement membrane

Figure 10.5 The mucociliaiy escalator

Basement membrane

Figure 10.5 The mucociliaiy escalator

2% mucin, 1% carbohydrate, less than 1% lipid and 0.03% DNA. Pulmonary secretions are slightly hyperosmotic, but that secreted from the smaller bronchi and bronchioles are thought to be isosmotic, being in equilibrium with tissue and vascular fluids. The pH of rat tracheal secretions has been reported to be between 6.0 and 7.6.

Increased mucus secretion is brought about by cholinergic and a-adrenergic agonists which act directly on the mucus secreting cells of the submucosal gland. Serous secretions are stimulated by b-agonists or cholinergic stimulation, whereas the goblet cells do not appear to be innervated. The peripheral granules, in which the mucus is stored, are discharged continuously and form a reservoir which is secreted after exposure to an irritant stimulus. Disease states can drastically change the distribution of goblet cells and composition of respiratory tract fluids. Conditions such as chronic bronchitis are characterized by increased sputum and chronic irritation, leading to an increased number of glandular and goblet cells which result in a crowding of ciliated cells. Mucus transport is thus slowed and the increased viscosity of the mucus exacerbates the problem.

Lung defenses

The respiratory tract possesses a complicated but comprehensive series of defenses against inhaled material due to its continual exposure to the outside environment. The lung has an efficient self-cleansing mechanism referred to as the muco-ciliary escalator (Figure 10.5). The mucus gel layer floats above the sol layer which has been calculated to be approximately 7 pm thick. The cilia extend through this layer so that the tip of the villus protrudes into the gel. The co-ordinated movement of the cilia propels the mucous blanket and deposited foreign materials at the rate of 2-5 cm min-1 towards the pharynx where they are swallowed. It has been estimated that 1 litre of mucus is cleared every 24 hours. Cigarette smokers demonstrate a considerable slowing in the clearance mechanisms of the large airways, resulting in an accumulation at the hilius, the junction between the lymph node and efferent lymphatic vessel.

The alveolar phagocytes or "dust cells" remove inhaled particles which reach the alveoli since this region is not ciliated. These cells can ingest and destroy bacteria and viruses and engulf inhaled particulates, migrating to the ciliated areas of the bronchial tree, where they are transported up the muco-ciliary escalator. Some macrophages with engulfed particles slowly penetrate the alveolar wall, especially in the region of the alveolar duct, pass into the tissue fluid and lymphatics. They also secrete chemicals that attract white blood cells to the site, and hence they can initiate an inflammatory response in the lung. Particles picked up by macrophages are removed by them into the lymphatic system of the lung and stored in adjacent lymph glands. Soluble particles are removed into the bloodstream, to be finally excreted by the kidney.

The composition of expectorated liquid and sputum varies, but consists of tracheobronchial, salivary, nasal and lacrimal gland secretions plus entrapped foreign material, dead tissue cells, phagocytes, leucocytes, alveolar lining and products of microbial infections.

Lung surfactant

The elastic fibres of the lung and the wall tension of the alveoli would cause the lung to collapse if this were not counterbalanced by the presence of the lung surfactant system. This covers the alveolar surface to the thickness of 10 to 20 nm. The surfactant has a liquid crystalline or gel structure which consists of phospholipids (74%), mucopolysaccharides and possibly proteins. It forms a continuous covering over the alveoli and is constantly renewed from below. Fifty percent of the surfactant comprises of dipalmitoyl lecithin, replacement of which is rapid with a half-life of 14 hours. Enzymes, lipids and detergents can destroy the surfactant. If the surfactant is removed by irrigation of the lung with saline, no harm appears to result since it is rapidly replaced. Generation of surfactant in neonates does not occur until the time of birth, so preterm infants often suffer from respiratory problems. Replacement surfactants, such as Exosurf® (GlaxoWellcome) can be administered to alleviate this problem.

Blood supply

The pulmonary artery arises from the right ventricle of the heart and thus supplies the lung with de-oxygenated blood. The lung tissue itself receives a supply of oxygenated blood from the bronchial arteries. Smaller capillaries branch from the main arteries to supply the terminal bronchioles, respiratory bronchioles, alveolar ducts, air sacs and alveoli. The average internal diameter of the alveolar capillary is only 8 pm with an estimated total surface area of 60 to 80 square metres and a capillary blood volume of 100 to 200 ml. The large surface area allows rapid absorption and removal of any substance which may penetrate the alveoli-capillary membrane thereby producing good sink conditions for drug absorption. Blood takes only a few seconds to pass through the lungs and it has been estimated that the time for passage through the alveolar capillaries of males at rest to be about 0.7 s, falling to 0.3 s on exercise.

Lymphatic system

In the adult lung, the lymphatic channels surround the bronchi, pulmonary arteries and veins. A deep system of lymphatics has been identified which lie adjacent to the alveoli. Movement of fluid from the alveolar lumen to the lymphatics has been described as a two-stage process. The first step is the passage across the epithelial lining through the intercellular clefts and/or through the cytoplasmic layer by diffusion or pinocytosis. The second step is the movement of fluid along the alveolar wall into the lymphatic area.

Nervous control

Both sympathetic and parasympathetic nerves supply the tracheo-bronchial tree. The primary role of these nerves is the control of ventilation of the lungs under varying physiological demand and the protection of the lung by the cough reflex, bronchoconstriction and the secretion of mucus. The lung is heavily innervated, as are the smooth muscle sheets that surround the airways, the intercostal muscles and the diaphragm.

Stimulation of the sympathetic nerves via the E2 adrenergic receptors primarily results in active relaxation of bronchial smooth muscle. Stimulation of parasympathetic nerves via the nicotinic and muscarinic receptors results in increased glandular activity and constriction of bronchial smooth muscle.

Cough reflex

Cough is accomplished by suddenly opening the larynx during a brief Valsalva manoeuvre which is a forceful contraction of the chest and abdominal muscles against a closed glottis. The resultant high-speed jet of air is an effective means of clearing the airways of excessive secretions or foreign particles. Cough receptors are found at the carina (the point at which the trachea divides into the bronchi) and bifurcations of the larger bronchi. They are much more sensitive to mechanical stimulation, and inhalation of dust produces bronchoconstriction at low concentration and elicits the cough reflex with larger amounts. Lung irritant receptors, located in the epithelial layers of the trachea and larger airways, are much more sensitive to chemical stimulation and produce a reflex bronchoconstriction and hyperpnoea (over respiration) on stimulation by irritant gases or histamine. The constriction is relieved by isoprenaline or atropine which suggests that the effect is due to contraction of smooth muscle, mediated through post-ganglionic cholinergic pathways.

Biochemical processes which occur in the lung

Almost all of the drug-metabolizing enzymes found in the liver are also present in the lung, although in much smaller amounts. The lung has been observed to be responsible for the release of 5-hydroxytryptamine, synthesis of prostaglandins, conversion of angiotensin I to angiotensin II, histamine release, and inactivation of bradykinin. The mast cells located around the small blood vessels and in the alveolar walls are rich in histamine, heparin, 5-hydroxytryptamine and hyaluronic acid. Histamine release accounts for many of the symptoms of bronchial asthma and allergies. It causes capillary dilatation, increased capillary permeability, contraction and spasm of smooth muscle, skin swelling, hypotension and increased secretion of saliva, mucus, tears and nasal fluids.

The mammalian lung can actively synthesize fatty acids, particularly palmitic and linoleic, and incorporate these into phospholipids which are predominantly saturated lecithins. The active synthesis of proteins by the alveolar cells has also been reported.

Breathing

Breathing is an automatic and rhythmic act produced by networks of neurons in the hindbrain (the pons and medulla). The respiratory rhythm and the length of each phase of respiration are set by reciprocal stimulatory and inhibitory interconnection of these brainstem neurons.

The forces that normally cause changes in volume of the chest and lungs stem not only from muscle contraction but also from the elastic properties of both the lung and the chest. A lung is similar to a balloon, it resists stretch, tending to collapse almost totally unless held inflated by a pressure difference between its inside and outside. Air moves in and out of the lungs in response to differences in pressure. When the air pressure within the alveolar spaces falls below atmospheric pressure, air enters the lungs (inspiration), provided the larynx is open; when the air pressure within the alveoli exceeds atmospheric pressure, air is blown from the lungs (expiration). The flow of air is rapid or slow in proportion to the magnitude of the pressure difference. Atmospheric pressure remains relatively constant, hence flow is determined by how much above or below atmospheric pressure the pressure within the lungs rises or falls.

The respiratory pump is versatile, capable of increasing its output 25 times, from a normal resting level of about 6 L min-1 to 150 L min-1 in adults.

Respiratory disease

The respiratory tract is the site of an exceptionally large range of disorders since it is exposed to the environment and therefore dust or gases in the air may cause damage to the lung tissue or produce hypersensitivity reactions. Secondly, the entire output of the heart has to pass through its large network of capillaries, hence diseases that affect the small blood vessels are likely to reach the remainder of the lung. Cough is a particularly important sign of all diseases that affect any part of the bronchial tree. The presence of blood in the sputum is an important indication of disease. It may result simply from an exacerbation of an existing infection, it may also indicate the presence of inflammation, capillary damage, tumour or tuberculosis.

Asthma

Particles of foreign protein may be deposited directly in the lung and hence it is not surprising that allergic reactions are very common. The most common and most important of these is asthma. The most common triggers are pollens, mold spores, animal proteins of different kinds, and proteins from a variety of insects, particularly cockroaches and mites that occur in house dust. Spasmodic asthma is characterized by contraction of the smooth muscle of the airways and, in severe attacks, by airway obstruction from mucus that has accumulated in the bronchial tree resulting in difficulty in breathing.

Extrinsic asthma is caused by an identifiable allergen, in which antigens affect tissue cells sensitized by a specific antibody. Intrinsic asthma occurs without an identifiable antigen or specific antibody. Extrinsic asthma commonly manifests in childhood because of a genetic predisposition or "atopic" characteristic. Hayfever and asthma are common atopic conditions. Exacerbation of extrinsic asthma is precipitated by contact with any of the proteins to which sensitization has occurred; airway obstruction is often worse in the early hours of the morning, for reasons not yet entirely elucidated. Intrinsic asthma may develop at any age, and there may be no evidence of specific antigens. Persons with intrinsic asthma experience attacks of airway obstruction unrelated to seasonal changes, although it seems likely that the airway obstruction may be triggered by infections, which are assumed to be viral in many cases.

Acute bronchitis

Acute bronchitis most commonly occurs as a consequence of viral infection. It may also be precipitated by acute exposure to irritant gases, such as chlorine, sulphur dioxide and ammonia. The bronchial tree in acute bronchitis is reddened and congested and minor blood streaking of the sputum may occur. Most cases of acute bronchitis resolve over a few days and the mucosa repairs itself.

Chronic bronchitis

This is a common condition and is generally produced by cigarette smoking and characterized by chronic cough and excess sputum production. The mortality rate from chronic bronchitis and emphysema soared after World War II in all western countries. The number and size of mucous glands lining the large airways increase after a number of years of smoking. The speed at which this occurs may be enhanced by breathing polluted air and by a damp climate. The changes are not confined to large airways, though these produce the dominant symptom of chronic sputum production. Changes in smaller bronchioles lead to obliteration and inflammation around their walls. All of these changes together, if severe enough, can lead to disturbances in the distribution of ventilation and perfusion in the lung, causing a fall in arterial oxygen tension and a rise in carbon dioxide tension. By the time this occurs, the ventilatory ability of the patient, as measured by the velocity of a single forced expiration, is severely compromised. It is not clear what determines the severity of these changes, since many people can smoke for decades without evidence of significant airway changes, while others may experience severe respiratory compromise after 15 years or less of exposure.

Pulmonary emphysema

This irreversible disease consists of destruction of alveolar walls and the consequent increase in size of the air spaces distal to the terminal bronchiole. It occurs in two forms, centrilobular emphysema, in which the destruction begins at the centre of the lobule, and panlobular (or panacinar) emphysema, in which alveolar destruction occurs in all alveoli within the lobule simultaneously. In advanced cases, the destruction is so great, that the two forms cannot be distinguished. Centrilobular emphysema is the form most commonly seen in cigarette smokers, and some observers believe it is confined to smokers. It is more common in the upper lobes of the lung (for unknown reasons) and probably causes abnormalities in blood gases out of proportion to the area of the lung involved by it. By the time the disease has developed, some impairment of ventilatory ability has occurred. Panacinar emphysema may also occur in smokers, but it is the type of emphysema characteristically found in the lower lobes of patients with a deficiency in the antiproteolytic enzyme known as alpha 1-antitrypsin. Like centrilobular emphysema, panacinar emphysema causes ventilatory limitation and eventually blood gas changes. Other types of emphysema, of less importance than the two major varieties, may develop along the dividing walls of the lung (septal emphysema) or in association with scars from other lesions.

Bronchiectasis

Bronchiectasis consists of a dilatation of major bronchi. It is believed usually to begin in childhood, possibly after a severe attack of whooping cough or pneumonia. The bronchi become chronically infected, and excess sputum production and episodes of chest infection are common. The disease may develop as a consequence of airway obstruction or of undetected (and therefore untreated) aspiration into the airway of small foreign bodies such as plastic toys.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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