Which airways are most susceptible to airway obstruction in patients with copd?

Histopathology

Small-airway disease is characterised by bronchiolar goblet cell hyperplasia.118 This takes place at the expense of Clara cells,119 which, together with the serous cells of the bronchial glands, secrete an airway-specific low-molecular-weight protease inhibitor (antileukoprotease), which is a potent protective factor against the development of emphysema.104,120–123 There is also inflammation in the smaller bronchi and bronchioles. Similar chronic inflammatory changes to those affecting the larger airways in chronic bronchitis are observed in the walls and adjacent tissues of bronchioles and small bronchi, the predominant cell again being the CD8-positive T lymphocyte.124 Wall thickening125 and fibrosing peribronchiolitis126 (Fig. 3.11) lead to the lumen becoming severely reduced: this causes irreversible obstruction and severe airflow limitation. The narrowing takes the form of focal stenoses.127 Proximal to the stenoses the bronchioles are often dilated. Bronchographic medium pools in the dilated segments, giving what has been described as a ‘mimosa flower’ effect,128 and there is an absence of peripheral filling.129 The focal stenoses are difficult to identify in random sections but are well demonstrated in plastic casts of the airways (Fig. 3.12).130,131 Alternatively, quantitative methods may be employed: these show both organic narrowing and mucus plugging of small airways.132 It is likely that cases of small-airway disease were included among the patients with chronic lung diseases studied by McLean.133–135 In many smokers peribronchiolar inflammation and fibrosis involve the more distal respiratory bronchioles and thicken the walls of adjacent alveoli so that there is restrictive as well as obstructive lung disease. This so-called respiratory bronchiolitis-associated interstitial lung disease overlaps with yet another effect of cigarette smoking, namely desquamative interstitial pneumonia, and is dealt with on page 313.

Complications

Patients with small-airway disease are prone to develop cor pulmonale, mainly as a result of widespread hypoxic pulmonary vasoconstriction and the consequent rise in pulmonary vascular resistance. Hypoxic pulmonary hypertension is dealt with on page 424. A further consequence of the hypoxia is a compensatory polycythaemia, the resultant haemoconcentration adding to the increased cardiac burden. Whilst death from small-airway disease is usually due to right-sided heart failure, obstructive respiratory failure and bronchopneumonia also contribute. These conditions are often present in combination.

Small Airway Disease

HRCT has the ability to demonstrate abnormalities of small airways having a diameter of a few millimeters or less.∗ Abnormalities that can be diagnosed include (1) inflammatory forms of bronchiolitis, such as cellular bronchiolitis (usually due to infection [Fig. 20.32A], aspiration, or hypersensitivity pneumonitis [seeFigs. 20.23 and 20.32B]), respiratory bronchiolitis (seeFig. 20.32C), follicular bronchiolitis, and panbronchiolitis (seeFig. 20.32D), and (2) small airway diseases associated with airflow obstruction (e.g., constrictive bronchiolitis; seeFig. 20.32E–F).269 (Cryptogenic organizing pneumonia has been previously classified as a disease of the small airways but is now considered an idiopathic interstitial pneumonia.163,246,269) The use of postexpiratory HRCT is particularly important in the diagnosis of small airway diseases because air trapping may be visible in the absence of other abnormalities (seeFig. 20.26B–C andeFig. 140.3).223,224 Postexpiratory HRCT may be performed by imaging after a forced vital capacity maneuver (

c. Bronchi and Bronchioles.

Bronchi and large bronchioles are similar histologically to the trachea. The cartilaginous structures decrease with decreasing bronchial diameter and are no longer present in bronchioles. The muscularis develops into a complete ring of smooth muscle encircling bronchi and bronchioles. In larger airways, the muscularis is interposed as a layer between the cartilaginous plates and the submucosa. The smooth muscle is geodesic, comprising two sets of fibers that wind along the bronchial tree as opposing spirals, thus causing the airway to both shorten and constrict as the muscle contracts. In some regions, airway caliber is regulated by the tone of this smooth muscle, which is controlled by nerves and pressor and depressor substances arising from the circulation and from airway epithelium. This prevents the mismatching of alveolar ventilation and vascular exchange units of the peripheral lung. As the bronchial diameter becomes smaller, the epithelium becomes flatter and the number of secretory cells decreases. Bronchioles no longer have submucosal glands or cartilage. The epithelium becomes simple columnar, with Clara cells replacing mucous cells and basal cells disappearing. Species differences exist in the proportion of ciliated to nonciliated cells, with the rat having approximately equal numbers of each. Terminal bronchioles are the most distal bronchioles that are not alveolarized and therefore the last of the conducting airways. In humans, macaques, dogs, cats, and ferrets, the terminal bronchiole ends in well-developed respiratory bronchioles, whereas in rodents, cattle, sheep, and pigs the terminal bronchiole ends in alveolar ducts or very short rudimentary respiratory bronchioles. In the respiratory bronchioles, the epithelium becomes cuboidal and alveoli open into their lumina. Bronchioles end in alveolar ducts, which contain spiral smooth muscle and are lined by alveolar epithelium. Alveoli open into the alveolar ducts. The acinar unit consists of the terminal bronchiole and all the air spaces supplied by it (Fig. 2). The bronchiole-alveolar duct junction (BADJ) is a vulnerable site for damage by low to moderate concentrations of many inhaled toxicants, both gaseous and particulate.

Large and Small Airways Disease in COPD

Chronic bronchitis often coincides with emphysema in patients with COPD, but it may occur independently from either emphysema or COPD and is defined in clinical terms (described earlier). Cigarette smoking is the major cause, although exposure to pollutants such as dust and smoke may play a role. Pathologic findings are goblet cell hyperplasia, mucus hypersecretion and plugging, and airway inflammation and fibrosis (Fig. 16.3).

The disease mechanisms involved in the development of emphysema are also important in the pathogenesis of chronic bronchitis. However, in contrast to emphysema, chronic bronchitis is a disease of the large airways and not of the lung parenchyma. Therefore, the relationship of chronic bronchitis to airflow obstruction is less robust than for emphysema, and airflow limitation consistent with COPD in a patient with symptoms of chronic bronchitis may be more reflective of concomitant emphysema and small airways disease. Inflammation in chronic bronchitis leads to effects on the airway epithelium, including excess mucus production and impairment in mucociliary clearance.

Neurogenic stimuli are also important in the pathogenesis of airway obstruction in chronic bronchitis. The conducting airways are surrounded by smooth muscle, which contains adrenergic and cholinergic receptors. Stimulation of β2-adrenergic receptors by circulating catecholamines dilates airways, whereas stimulation of airway irritant receptors constricts airways through a cholinergic mechanism by means of the vagus nerve. The irritant bronchoconstrictive pathways are normally present to protect against inhalation of noxious agents, but in pathologic states these pathways may contribute to airway hyperreactivity. A host of endogenous chemical mediators such as proteases, growth factors, and cytokines can also affect airway tone.

By definition, the predominant symptom in chronic bronchitis is sputum production. Bronchospasm may also be prominent. Recurrent bacterial airway infections are typical. As with patients with COPD, the evaluation of patients with chronic bronchitis should include pulmonary function tests and a chest radiograph in addition to standard laboratory testing.

Damage to the small airways (those less than about 2 mm in diameter) is integral to the pathogenesis of COPD. The small airways are the major site of resistance to airflow in COPD. Respiratory bronchiolitis, in which there is an accumulation of pigmented macrophages in and around the bronchioles (E-Fig. 16.5

Respiratory Bronchiolitis

A distinct small-airway disease occurring almost exclusively in cigarette smokers, respiratory bronchiolitis (RB) is characterized histopathologically by accumulations of pigment-laden macrophages within membranous and respiratory bronchioles (Figs 21.9 and 21.10). There are also rare case reports of RB developing in nonsmokers exposed to asbestos and nonasbestos dusts or fumes. On iron stain, the cytoplasm of the tan-colored macrophages is faintly positive with a dusty appearance, distinct from the much coarser and brightly staining granules of hemosiderin pigment (Fig. 21.11). RB bears a close relationship to RB-ILD and to desquamative interstitial pneumonia (DIP). All of these disorders are highly linked to cigarette smoking and share the feature of pigmented macrophages in airspaces, but the anatomic distributions of the macrophage infiltrates differ: bronchiolar in RB, bronchiolar and peribronchiolar in RB-ILD, and primarily alveolar in DIP. The latter two entities are best categorized as interstitial lung diseases. (Please see Chapter 16 for a more in-depth discussion of these entities.)

60.2.3 Small Airway Disease

COPD also includes small airway disease—a poorly understood entity that includes inflammation of the terminal and respiratory bronchioles as well as fibrosis of airway walls with narrowing (8). Some inflammation of the terminal and respiratory bronchioles is likely present in all cigarette smokers. However, only a subset of smokers develops fibrosis and narrowing of the small airways, with associated airflow obstruction.

The classification of disease processes encompassed within COPD emphasizes the heterogeneity of this disorder. Some investigators have attempted to define subsets of COPD based on clinical and/or physiological criteria. For example, Burrows suggested that chronic airflow obstruction included a group of patients with emphysema, who were largely male smokers with progressive airflow limitation, and a group of patients with chronic asthmatic bronchitis, who were largely female with a more benign clinical course (9). However, dissection of the syndrome of COPD will likely require improved understanding of the pathophysiological basis of disease, and, potentially, the genetic determinants of this condition (10).

Cells of the Pulmonary Parenchyma

Alveoli arise from the respiratory bronchioles and the alveolar ducts. The alveolar septum or wall consists of three components: epithelium (which lines the alveolus or air space), interstitium, and capillary endothelium. Gas exchange occurs in the alveoli across the thin epithelial lining and adjacent endothelium (air-blood barrier) (Figure 6.4).

The major cell types are the epithelial type I and type II cells, the pulmonary endothelial cells, interstitial cells, and macrophages. Type I cells constitute 8% to 11% of all cells found in the alveolar region, and type II epithelial cells constitute 13% to 16%. Tight junctions are present between epithelial cells. Epithelial cells lie on a continuous basement membrane, as do endothelial cells. In many places, the basement membrane of both cell types is fused, forming an extremely thin air–blood barrier. In other areas, the cells are separated by interstitium that consists of scant connective and elastic tissue and resident interstitial cells, macrophages, lymphocytes, plasma cells, and mast cells.

Alveolar type I epithelial cells are attenuated, highly-differentiated cells that do not divide; they cover approximately 90% to 95% of the alveolar surface. Since these cells have a large surface area, they are highly susceptible to injury. The main function of the type I cell is the maintenance of a barrier to prevent leakage of fluid and proteins across the alveolar wall into the air spaces, while allowing gases to freely cross the air–blood barrier.

The alveolar type II epithelial cells are cuboidal in shape, located in corners or niches between capillaries, and contain lamellar bodies in which surfactant is stored. The functions of type II cells include the synthesis, storage, and secretion of pulmonary surface-active material; the re-epithelialization of the alveolar wall after lung injury; and transepithelial solute transport to limit the volume of, and perhaps regulate the composition of, alveolar fluid.

The capillaries, which are lined by endothelial cells (30% to 42% of all cells), are of the closed type, without openings or fenestrations. Intercellular junctions between endothelial cells are characterized by zonulae occludens, but are less tight than the epithelial junctions. Therefore, unlike other tissues, the major permeability barrier in the lung is the alveolar epithelium.

Macrophages have been identified in three distinct locations in the lung: the interstitium, alveoli, and capillary lumen. Macrophages present in the alveolar interstitium are derived from bone marrow, can divide, and can either phagocytize particulate material that crosses the alveolar walls or move into the alveolar compartment to become alveolar macrophages. Another macrophage-like cell in the interstitium is the dendritic cell, which is specialized for antigen presentation and accessory function.

Alveolar macrophages (AMs) are derived from the interstitial compartment; however, they do divide and are a self-renewing population of cells. The intravascular macrophage (IVM) is present in humans, pigs, cats, horses, ruminants and marine mammals, but not in rodents or dogs (Figure 6.4). It is a fixed macrophage of the capillary bed, has specialized junctional complexes with adjacent endothelial cells; it is morphologically and, presumably, functionally similar to hepatic Küpffer cells. Intravascular macrophages function similarly to the AM. The IVMs account for some of the species differences that occur in response to pulmonary injury.

Fibroblasts are the major cell type present in the interstitium. Apart from maintaining the structural integrity of the lung and production of collagen and other matrix components, such as fibronectin, fibroblasts produce a variety of enzymes including collagenase, and other factors, such as prostaglandins and plasminogen activator, that may modulate the function of other cell types. Fibroblasts play a major role in disease processes that result in fibrosis.

What airways are affected by COPD?

What causes airway obstruction in COPD?

Where is the obstruction in COPD?

Is COPD a lower airway obstruction?