Small airway obstruction in COPD: new insights based on micro-CT imaging and MRI imaging

Abstract

The increase in total cross-sectional area in the distal airways of the human lung enhances the mixing of each tidal breath with end-expiratory gas volume by slowing bulk flow and increasing gas diffusion. However, this transition also favors the deposition of airborne particulates in this region because they diffuse 600 times slower than gases. Furthermore, the persistent deposition of toxic airborne particulates stimulates a chronic inflammatory immune cell infiltration and tissue repair and remodeling process that increases the resistance in airways <2 mm in diameter four to 40-fold in COPD. This increase was originally attributed to lumen narrowing because it increases resistance in proportion to the change in lumen radius raised to the fourth power. In contrast, removal of one-half the number of tubes arranged in parallel is required to double their resistance, and approximately 90% need to be removed to explain the increase in resistance measured in COPD. However, recent reexamination of this problem based on micro-CT imaging indicates that terminal bronchioles are both narrowed and reduced to 10% of the control values in the centrilobular and 25% in the panlobular emphysematous phenotype of very severe (GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade IV) COPD. These new data indicate that both narrowing and reduction in numbers of terminal bronchioles contribute to the rapid decline in FEV₁ that leads to severe airway obstruction in COPD. Moreover, the observation that terminal bronchiolar loss precedes the onset of emphysematous destruction suggests this destruction begins in the very early stages of COPD.

Figure 1.

A microCT scan of a terminal bronchiole branching into two first-order respiratory bronchioles (ie, transitional bronchioles) where alveolar openings first appear (reproduced with permission from McDonough et al). B, Bronchogram of a postmortem human lung where a cluster of terminal bronchioles are surrounded by a fibrous connective tissue septa to form a secondary lung lobule. C, A lobule as defined by Reid where the branching pattern switches from one where the branches are cm apart to one where the branches within the square are only mm apart. TB=terminal bronchiole.

Figure 2.

A, Bronchogram from a normal human lung to demonstrate that the pathways from the main stem bronchus to the alveoli vary substantially in length. B, A color-coded map of data replotted from Weibel to demonstrate the distribution of airways of different sizes within each generation of airway branching. C, Data from Horsfield and Cumming demonstrating that the intralobular branches (see Fig 1 for a description of a lobule) can be reached in as few as eight generations of branching when the shortest pathways are followed, that the mean number of branches required to reach the interlobular airways is approximately 14 and that it may take as many as 24 generations of branching when the longest pathways are followed.

Figure 3.

A, Data from Weibel showing the average airway diameter at each generation of branching measured directly from an airway cast. The red square with error bars shows the mean diameter of the terminal bronchioles measured by McDonough et al using microCT scan. B, Comparison of the total cross-sectional area of all the airways in each generation of airway branching measured by Weibel to the total cross-sectional area of the terminal bronchioles measured from microCT images by McDonough et al. C, A retrograde catheter (arrow) placed in a small airway approximately 2 mm in diameter in the manner described in References 7 and 13. D, Chest radiograph from a living human with normal lung function where the bronchial pressure-measuring device developed by Yanai and colleagues was put in place through a bronchoscope. The direct measurement of the resistance of the small airways <2 mm in diameter provided in both postmortem human lungs and in living humans are consistent with Weibel’s measurements of a rapidly increasing total cross sectional area of the distal airways.

Figure 4.

A, Normal lung lobule containing six terminal bronchioles. B, Leopold and Gough’s original diagram of a primary centrilobular emphysematous lesion described almost simultaneously by themselves in the UK and by McLean in Australia. C, Bronchogram of a centrilobular emphysematous space formed by the coalescence of several primary lesions. D, The electrical analog of the peripheral lung used by Otis et al, where S is the power source, R is resistance, and C is capacitance. E, Modification of the normal electrical analogue to include collateral channels R4, that have very high resistance in the normal lung and fall to very low levels in emphysematous regions of lungs affected by COPD. We postulate that the primary centrilobular lesions develop beyond surviving terminal bronchioles and that the fall in collateral resistance associated with emphysematous destruction provides ventilation to the normal alveoli located beyond destroyed terminal bronchioles. CLE=centrilobular emphysematous space.