The Contribution of Small Airway Obstruction to the Pathogenesis of Chronic Obstructive Pulmonary Disease

Abstract

The hypothesis that the small conducting airways were the major site of obstruction to airflow in normal lungs was introduced by Rohrer in 1915 and prevailed until Weibel introduced a quantitative method of studying lung anatomy in 1963. Green repeated Rohrer's calculations using Weibels new data in 1965 and found that the smaller conducting airways offered very little resistance to airflow. This conflict was resolved by seminal experiments conducted by Macklem and Mead in 1967, which confirmed that a small proportion of the total lower airways resistance is attributable to small airways <2 mm in diameter. Shortly thereafter, Hogg, Macklem, and Thurlbeck used this technique to show that small airways become the major site of obstruction in lungs affected by emphysema. These and other observations led Mead to write a seminal editorial in 1970 that postulated the small airways are a silent zone within normal lungs where disease can accumulate over many years without being noticed. This review provides a progress report since the 1970s on methods for detecting chronic obstructive pulmonary disease, the structural nature of small airways' disease, and the cellular and molecular mechanisms that are thought to underlie its pathogenesis.

FIGURE 1.

The embryonic phase of lung development (4–8 wk) begins with the formation of a groove (sulcus laryngotrachealis) in the ventral lower pharynx, after which the lung bud (true lung primodium) forms which further subdivides into the two main bronchi of which the left bronchus is directed more laterally establishing the asymmetry of the main stem bronchi that is present in adults. In the pseudoglandular phase (5–16 wk), all conducting airways are established (bronchi, bronchioles, and terminal bronchioles). These are lined with cuboidal cells which are the precursors of ciliated cells that can be found in humans from the 13th week of pregnancy. The canalicular phase (16–24 wk) is associated with the development of the pulmonary parenchyma consisting of respiratory bronchioles, alveolar ducts, alveolar sacs, and an invasion of capillaries around the acini for later gas exchange. There is also a significant differentiation of type II pneumocytes into attenuated type I pneumocytes. By the beginning of the saccular phase (25 wk), a large part of the amniotic fluid is produced by the lung epithelium. From this time the maturity of the lung can be measured clinically by the production of surfactant by type II pneumocytes. At the end of this phase, interstitial fibroblasts begin production of extracellular matrix in the interductal and intersaccular space. Over the last few weeks prior to birth, the first alveoli form, and after birth become increasingly complex through alveolarization with formation of secondary septae. Depending on the study, this process continues to the first or eighth year of life.

FIGURE 2.

A: bronchogram of a left lung to demonstrate the different pathway lengths to the periphery of the lung. B: distribution of airways of a given size in each generation of branching to demonstrate that each generation contains airways of several different sizes. [Data redrawn from Weibel (137).] C: total lumen cross-sectional area of all the branches decreases between generation 0–3 and then increases exponentially toward the periphery of the lung.

FIGURE 3.

A: bronchogram of the distal human lung to demonstrate Reid's original observation that in an individual pathway the airways branch points are initially centimeters apart, become closer to each other near the periphery of the lung, and end in clusters of branches (white rectangle) that are only millimeters apart. B: an image of one of these clusters taken through the pleural surface to show that it represents a secondary lobule first described by Miller as a group of preterminal bronchioles surrounded by fibrous connective tissue septa (black arrow) and a terminal bronchiole (white arrowhead) that opens into tuft-shaped respiratory bronchioles. C: a micro CT image at much higher magnification clearly demonstrates the junction between the terminal bronchiole and two first-order respiratory bronchioles (also termed transitional bronchioles) where the alveoli opening from them are visible. [From Hogg et al. (42a), with permission from Elsevier.]

FIGURE 4.

A simple model to illustrate that gas transport from the atmosphere to the blood circulating through the pulmonary capillaries depends on two fundamentally different processes: the bulk movement of gas along a pressure gradient developed by the respiratory muscles and the diffusion of gases along a concentration gradient developed by the exchange of oxygen and carbon dioxide at the alveolar surface. This creates an interface between bulk flow and diffusion that renders the smaller conducting airways and proximal respiratory bronchioles vulnerable to the deposition of fine particulates that remain suspended in the gas reaching the peripheral lung. Because these small particles do not diffuse as readily as the gases they are suspended in, they tend to settle and deposit on the lung surface in the regions where the shift from bulk flow to diffusion occurs.

FIGURE 5.

The laryngeal orifice creates turbulent airflow (curly arrows) which extends into the trachea and is reinforced at branch points in the central airways. The airflow through the trachea is divided among an ever increasing number of airway branches, causing the velocity of airflow through the individual branches to diminish until a fully developed pattern of laminar flow is established.

FIGURE 6.

A: an example of the changes in nitrogen concentration measured at the mouth during a single breath nitrogen washout (SBNW). The expiration that follows the inspiration of a single deep breath of 100% oxygen produces a flat phase 1 as the dead space empties. This is followed by an upward sloping phase 2 where the nitrogen concentration rises swiftly followed by a much more slowly rising alveolar plateau (phase 3). That is followed by phase 4 produced by closure of the airways supplying the better ventilated regions of the lung and a greater contribution from the regions that are less well ventilated which have a higher concentration of nitrogen. B: a multiple breath nitrogen washout curve (MBNW). Tidal volume (bottom panel) and expired nitrogen (top panel) are plotted against breath number. Each expiration has its own alveolar plateau. The alveolar plateaus for the 1st and 20th breath are shown in the inset normalized for the mean expired nitrogen concentration. The initial phase 3 slope is influenced by inhomogeneity in the acinar compartment, and the progressive increase in slope as a function of breath number is influenced by convective inhomogeneity. Calculating Sacin and Scond can indicate whether the origin of the inhomogeneity is in the peripheral or more central airways. [B from Verbanck et al. (127).]

FIGURE 7.

The maximum flow volume diagram. Inspiratory flow is unrestricted and entirely dependent on effort over the whole vital capacity range. Peak expiratory flow (PEF) or maximal expiratory flow (MEF) is also effort dependent, but after ∼10% of the vital capacity is exhaled, flow becomes fixed irrespective of the effort and measures derived from this portion of the curve include instantaneous flows at 75, 50, and 25% of vital capacity and maximal mid expiratory flow rate (MMEFR) or MEF 25–75. Note that the flow rates achieved at the end of the forced expiration are much lower than the flow rates achieved at the same lung volume on inspiration due to dynamic compression of the intrathoracic airways. (Copyright: “Flow-volume-loop” by SPhotographer–Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons: https://commons.wikimedia.org/wiki/File:Flow-volume-loop.svg#/media/File:Flow-volume-loop.svg)

FIGURE 8.

The changes in atmospheric particulate air pollution during the 41st Japanese expedition to the south pole. A: PM 0.3-0.2, PM 2.0–5.0, and PM 5.0 levels during the entire journey from Japan to Antarctica and return. B: total leukocyte count. C: segmented polymorphonuclear leukocyte (PMN) count. D: band-form PMN count that indicates the early release of PMN of the marrow. E: monocyte counts, over the same time periods that the air pollution was measured. Although there were differences in leukocyte counts between smokers (open squares) and nonsmokers (open triangles), these differences tended to disappear in Antarctica where the levels of air pollution were very low (please see the original report for the complete statistical analysis). [Modified from Sakai et al. (99).]

FIGURE 9.

A: box and whisker plot of the levels of PM 10 air pollution in Singapore from January 1996 to January 1997, to illustrate the sharp but still modest increase in air pollution that occurred between August and November due to the South East Asian haze of 1997. B: data from a group of military recruits that were undergoing basic training during the entire period of the haze where the data show a clear association between circulating PMN band cell forms and the level of particulate air pollution as the haze cleared. C: photomicrograph of the human bone marrow to illustrate the clear difference between band cell PMNs (yellow arrows) and mature PMNs. Importantly, the band cell PMNs only leave the marrow in small numbers compared with mature PMNs, and the rise in band cell counts shown in Figures 8 and 9 provides clear evidence that marrow output has been increased. Please see the original reference for the statistical analysis. [From Tan et al. (114). Reprinted with permission of The American Thoracic Society. Copyright 2016 American Thoracic Society.]

FIGURE 10.

Structural alterations that can be seen in the small airways in COPD. These include increased numbers of goblet cells and decreased numbers of Club (Clara cells) leading to mucus plugging, hyperplasia of smooth muscle, fibrosis of the airway wall, and bronchial-associated lymphoid tissue with intraepithelial lymphocytes that potentially capture antigens by interacting with microfold (M) cells or by extending transepithelial projections into the lumen.

FIGURE 11.

A diagram from Nagaishi's text book on the functional anatomy of the lung showing a secondary lymphoid organ (i.e., a lymph node) that has a capsule and afferent and efferent lymphatics, as well as tertiary lymphoid organs that are located beneath the epithelium of airways and endothelium of lymphatic vessels. The cellular content of the tertiary lymphoid organs is similar to that observed in lymph nodes, and they are capable of forming germinal centers and may be involved in local immunoregulation. [From Nagaishi (74).]

FIGURE 12.

A: a collection of bronchial lymphoid tissue with a lymphoid follicle containing a germinal center (GC) surrounded by a rim of darker-staining lymphocytes that extend to the epithelium of both the small airway and alveolar surface (Movat's stain, ×6). B: another follicle, in which the germinal center stains strongly for B cells (×6). C: a serial section of the same airway stained for CD4 cells, which are scattered around the edge of the follicle and in the airway wall (×6.5). D: an airway that has been extensively remodeled by connective tissue deposition in the subepithelial and adventitial compartments of the airway wall. The arrow points to the smooth muscle that separates the subepithelial from the adventitial compartments (Movat's stain, ×6). [From Hogg et al. (40), with permission from Massachusetts Medical Society.]