ArticlesPathophysiology of airflow limitation in chronic obstructive pulmonary disease
Introduction
The defining feature of chronic obstructive pulmonary disease (COPD) is irreversible airflow limitation measured during forced expiration,1, 2 caused by either an increase in the resistance of the small conducting airways,3, 4, 5 an increase in lung compliance due to emphysematous lung destruction,6 or both. The units for airway resistance are cm H2O/L per s and for compliance are L/cm H2O, and their product (time), provides the time constant for lung emptying.7 This constant is reflected in measurements of the volume of air that can be expired in one second (FEV1) and its ratio to forced vital capacity (FEV1/FVC), which are reliable screening tools because they are affected by both airway obstruction and emphysema.
Figure 1 reproduces classic data from Fletcher and colleagues8 showing the different rates of decline in FEV1 with age for non-smokers and smokers who either do or do not develop COPD. The horizontal lines have been added to show the boundaries of COPD severity recommended by a global initiative on obstructive lung disease (GOLD).1, 2 Fletcher and colleagues8 showed that the rate of decline in FEV1 of most people who smoke is similar to that for non-smokers, in that they remain in the GOLD 0 and 1 category with greater than 80% predicted FEV1. These investigators also showed that in a susceptible minority of tobacco smokers (estimated at 15–20% of the total), lung function declines rapidly to levels consistent with moderate (GOLD 2), severe (GOLD 3), and very severe (GOLD 4) COPD. Their data also showed that stopping smoking had a beneficial effect at any age. Findings based on post mortem examination,9, 10 resected lung specimens,11, 12 biopsies,13 induced sputum,13, 14 and bronchoalveolar lavage,13, 15 all indicate that the lung inflammation is present in everyone with a tobacco smoking habit. The reason why only a minority of smokers experiences an excessive decline in FEV1 is unknown, but preliminary evidence suggests that the lung inflammatory response is amplified in the susceptible group.12, 16 The purpose of this review is to discuss the nature of the lesions associated with airflow limitation in terms of the host defence of the lung.
Section snippets
Host defence of the lung
The cause of COPD is attributed to the total burden of toxic gases and particles that individuals inhale during their lifetime.1, 2 Although atmospheric pollution contributes to this burden, the smoking of tobacco products is the major risk factor.1, 2, 17 The host defence system against this type of insult is provided by the innate and adaptive inflammatory and immune response.
Innate response
The innate defence system includes mucociliary clearance of the airways, which works cooperatively with the monocyte/macrophage system to move deposited particles up the mucociliary escalator.18, 19 Additionally, tight junctions connecting lung epithelial cells provide a physical barrier between the tissue and airspace. This protective barrier is broken down by chronic exposure to cigarette smoke,20, 21, 22 and this epithelial disruption initiates an acute inflammatory response. The
Adaptive response
The innate system can recognise antigens deposited on the lung surface and react to them but it has a limited memory of previous exposure.31 By contrast, the cellular and humoral immune components of the adaptive response have exquisite memory for both soluble and particulate antigens that are aspirated or inhaled into the lung.32, 33, 34, 35, 36 Antigens deposited on the epithelial surface of the airways may either be transported across the intact epithelium in specialised epithelial M cells
Antigen presentation links innate and adaptive responses
The lymphoid follicles in the BALT and regional lymph nodes (figure 2C and D) greatly enhance the opportunities for antigen presentation, which is the critical link between the innate and adaptive response. Lymphocytes migrate out of the blood at the venous end of the microvasculature that supplies the follicle (figure 2D) by attaching to specialised high endothelial cells that line the venules.37 The B cells leaving the blood accumulate near the edge of the follicles and the T cells accumulate
Cytokine control of host response
Two important cytokines (tumour necrosis factor (TNFα and interleukin 1β) initiate and orchestrate the innate response and have a broad stimulating effect on the B and T cells needed to develop an adaptive response.23, 28, 44 Experiments designed to overexpress these two cytokines individually have shown that both induce a substantial local inflammatory reaction that disappears when cytokine expression stops. But only interleukin 1β overexpression stimulates the collagen deposition associated
Pathology of COPD
The lungs of people that smoke 1–2 packages of cigarettes per day receive a cyclic exposure to toxic gases and particles that is repeated 20 to 40 times every day. Those with a 50 pack-year smoking history receive this type of daily stimulus for 25–50 years. The cough and sputum production that are the defining features of chronic bronchitis are a manifestation of the innate response to the toxic particles and gases in cigarette smoke. But the airflow limitation that defines COPD is associated
Chronic bronchitis
The inflammation associated with chronic bronchitis is located in the epithelium of the central airways (larger than 4 mm in internal diameter) where it extends along the gland ducts into the mucus-producing glands.59, 60 This inflammatory process is associated with increased production of mucus, defective mucociliary clearance, and disruption of the epithelial barrier provided by the innate host defence system.20, 21, 22 Inflammatory cells from both the innate and adaptive host response
Small airway obstruction
Although the terms chronic bronchitis and airway obstruction are often used interchangeably, the major site of obstruction is actually found in the smaller conducting airways (less than 2 mm in diameter).3, 4, 5 These airways are spread out between the fourth and 14th generation of airway branching, since the human bronchial tree branches in a non-dichotomous fashion.73 The increase in the numbers of airways with progressive branching rapidly expands their total cross sectional area and lowers
Emphysema
Emphysematous lung destruction reduces maximum expiratory flow by decreasing the elastic recoil force available to drive air out of the lung.6 The lesions produced by emphysema were first described by Laennec100 and are defined by dilatation and destruction of lung tissue beyond the terminal bronchiole.101, 102 The practice of examining the postmortem lung in the inflated state led to the modern descriptions of the various forms of emphysematous lung destruction.103, 104, 105, 106, 107, 108, 109
Leucocyte kinetics in smokers
One possibility is that the effect of smoking on leucocyte kinetics increases the numbers of these cells in lung tissue. A cardiac output of 6 L/min distributes about 8640 L of blood to the lung in the pulmonary circulation every 24 h, and an additional 86 L (about 1% of the cardiac output) is delivered by the systemic bronchial vessels. Since each litre of blood contains about 109 leucocytes, about 8·7×1012 leucocytes flow through the lung every day. Both direct observations of the pleural
Small-airway-obstructive and emphysema phenotypes of airflow limitation
Progress toward specific treatments for COPD might be accelerated by moving beyond measurements of airflow limitation to the precise diagnosis of the specific targets responsible for the airflow limitation. This step will require precise, safe, non-invasive quantitative methods of diagnosis that will allow both the airway-obstructive and emphysema phenotypes to serve as measurable endpoints in clinical trials. The introduction of CT scanning has provided an objective method for measuring the
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