Elsevier

The Lancet

Volume 364, Issue 9435, 21–27 August 2004, Pages 709-721
The Lancet

Articles
Pathophysiology of airflow limitation in chronic obstructive pulmonary disease

https://doi.org/10.1016/S0140-6736(04)16900-6Get rights and content

Summary

The airflow limitation that defines chronic obstructive pulmonary disease (COPD) is the result of a prolonged time constant for lung emptying, caused by increased resistance of the small conducting airways and increased compliance of the lung as a result of emphysematous destruction. These lesions are associated with a chronic innate and adaptive inflammatory immune response of the host to a lifetime exposure to inhaled toxic gases and particles. Processes contributing to obstruction in the small conducting airways include disruption of the epithelial barrier, interference with mucociliary clearance apparatus that results in accumulation of inflammatory mucous exudates in the small airway lumen, infiltration of the airway walls by inflammatory cells, and deposition of connective tissue in the airway wall. This remodelling and repair thickens the airway walls, reduces lumen calibre, and restricts the normal increase in calibre produced by lung inflation. Emphysematous lung destruction is associated with an infiltration of the same type of inflammatory cells found in the airways. The centrilobular pattern of emphysematous destruction is most closely associated with cigarette smoking, and although it is initially focused on respiratory bronchioles, separate lesions coalesce to destroy large volumes of lung tissue. The panacinar pattern of emphysema is characterised by a more even involvement of the acinus and is associated with α1 antitrypsin deficiency. The technology needed to diagnose and quantitate the individual small airway and emphysema phenotypes present in people with COPD is being developed, and should prove helpful in the assessment of therapeutic interventions designed to modify the progress of either phenotype.

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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