Effects of Drugs on Small Airways

ANN J. WOOLCOCK

Institute of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

	INTRODUCTION

TOP INTRODUCTION CONCLUSION REFERENCES

A literature search using the words "asthma, airways, small, peripheral, drugs, treatment, and human" reveals almost no papers. Patel and colleagues (1) used monodispersed isoproterenol of two different particle sizes and measured the dose response of the forced expiration. They found a greater difference in the response to the smaller (2.5 µm) particles than to the larger (5.0 µm) particles, and this difference was greater for measures of FEF_25-75 than measures of FEV₁. They interpreted the result as demonstrating that the smaller particles were having a greater overall effect because of their effect on the small airways. This may not be a correct interpretation of the data, as it is not possible to distinguish changes in the small airways, as opposed to the large airways, from tests of forced expiration. Nevertheless the authors raised the issue of a potential differential effect of inhaled drugs on small and large airways. There appear to be no reports concerning the effects on the small airways of other drugs commonly used to treat asthma. This paucity of data probably results from the difficulty of measuring the function of the small airways in humans. Thus, in this article the evidence for involvement of the small airways is reviewed, the difficulties in demonstrating the effects of drugs with presently available tests is discussed, and some approaches that might be taken in the future are suggested.

	INVOLVEMENT OF THE SMALL AIRWAYS

In discussing the effects of drugs it is important to discuss the abnormalities of the small airways that drugs could affect. With our present understanding of asthma, this means the extent of inflammation in the small airways and the degree to which these airways narrow and dilate in response to various constricting agents and drugs.

Inflammation

Preceding papers in this supplement have documented the inflammation in the small airways in asthma. It is also clear that these airways are involved in the severe changes that cause asphyxia and death, as shown in Figures 1 and 2. The first is an airway from a young patient who died suddenly of asthma, while Figure 2 shows a periodic acid-Schiff stain of an older patient with chronic asthma who died during a severe exacerbation. The airways, which were representative of the whole of both lungs at autopsy, are completely filled with mucus. If this situation was present in life, inhaled drugs would be totally ineffective. It is not clear if the plugging, which is almost always found in death due to asthma, is a terminal event or if it is present for days before death. In patients with near-fatal attacks, it is difficult to detect mucus either from the sound of the cough or from the noise made by air passing through the airways. However, apart from the plugs it is clear that the small airways are involved in the same inflammatory processes as the large airways in the terminal events of fatal asthma; to treat the inflammation, it is necessary that corticosteroids reach both sites.

View larger version (116K): [in this window] [in a new window]   Figure 1.   A small airway from a 22-yr-old who died from an acute attack of asthma.

View larger version (117K): [in this window] [in a new window]   Figure 2.   Two small airways from an older person who died after a long history of asthma. The stain is periodic acid-Schiff.

The structure of the large and small airways and the nature of the inflammatory infiltrate has been studied systematically by Carroll and colleagues in fatal asthma, nonfatal asthma, and nonasthmatic airways (2). Figure 3 shows the inner wall area, expressed as mm² per mm of basement membrane, in airways of differing sizes. In airways smaller than 4 mm basement membrane perimeter, the inner wall was significantly thicker in both asthmatic groups compared with the control group, and the nonfatal asthma group tended to have even thicker airways than those in the fatal asthma group. This demonstrates clearly that the inner wall (that area between the airway smooth muscle and the basement membrane) of the very small airways is thickened in asthma.

View larger version (18K): [in this window] [in a new window]   Figure 3.   The inner wall area, expressed as mm2 per mm of basement membrane perimeter (Pbm) in different-sized airways. Reproduced from Carroll and colleagues (3).

After sectioning a considerable number and range of airways, Carroll and colleagues (2) concluded that the airway structure and inflammatory cell numbers were uniform throughout the bronchial tree in normal and asthmatic subjects. A number of other studies also show that there is as much inflammation in the small as in the large airways (5, 6). Therefore, small samples of the large or small airways are likely to be representative of all the airways. If these studies are correct, samples from the small airways obtained with transbronchial biopsies could be representative of the small airways as a whole, thus minimizing the number of biopsies required to determine the effect of drugs on the small airways.

The processes that lead to inflammation of the airways are not understood in allergic airway disease. It is thought that the inflammation results from the reaction of the airway cells to inhaled allergen. The size of allergen-carrying particles in the environment is not yet well defined but, if they reach all of the small airways, they must be extremely small. Alternatively, inflammation might start in larger airways, where larger allergen-carrying particles are deposited, and then extend peripherally in a way that is not understood.

Inflammation can be confined mostly to the small airways (as is the case with the inflammation caused by cigarette smoke) with little involvement of the large airways. This could result in relatively few symptoms of asthma and remain unnoticed. Such limited inflammation may be the cause of the chronic airflow limitation that is often seen in older nonsmoking women who have no history of asthma and no symptoms until they become breathless and develop a cough after the age of 50 yr.

Narrowing and Dilatation

Ten years ago Armour, Black, and Berend (7) studied peripheral strips from human lungs. These strips contained smooth muscle, almost all of which was in the small airways. They were able to demonstrate contraction with carbachol and both relaxation and contraction with histamine. They were unable to show any correlation between in vivo airway responsiveness to methacholine studied by inhalation challenge and the in vitro sensitivity. However, these experiments clearly showed that human small airways can narrow and dilate and are responsive to agents that affect airway smooth muscle tone.

	DIFFICULTIES IN DEMONSTRATING CHANGES IN FUNCTION OF THE SMALL AIRWAYS

Lung Function Tests

Forced expiratory flow is determined by the elastic recoil of the lungs, the resistance of the airways, and the degree to which the large airways are compressed during the forced maneuver. When the flow-volume curve is concave and the flow rates during the last part of the volume are low, this profile can be interpreted as narrowing of the small airways only if it has also been demonstrated that the elastic recoil of the lungs is normal, that the airway resistance is normal (excluding narrowing of the large airways), and that there is no difference between breaths of maximal and submaximal expiratory effort. In practice, these other tests are not usually performed. In any case, in asthma the large airways are nearly always involved to some extent, so determining the presence of narrowing of the small airways is extremely difficult from tests of forced expiration.

When the FEV₁ is entirely normal, the best test for detecting an abnormality in the small airways is probably the single-breath nitrogen test (SBNT). If the slope of phase III or the closing volume is increased, the small airways are likely to be involved (8). Figure 4 shows an example of the SBNT performed before and after a bronchial challenge with histamine (9). After 15 min the FEV₁ had fallen from 3.1 L to 1.8 L; 45 min later, during recovery, it had improved to 2.1 L; and after administration of a bronchodilator, it returned to 3.1 L. In this particularly young patient with moderately severe asthma, the slope of phase III and the closing volume were normal, suggesting little abnormality in the small airways. However, it did not take very much histamine to make his airways constrict and for severe maldistribution of ventilation to occur. We did not expect to see such marked changes or such rapid recovery. However, after bronchodilation the slope of the phase III remained abnormally high. Although these findings probably result from differences in narrowing throughout the lungs, they show that it is possible to use the SBNT to examine the small airways in someone with quite severe airway hyperresponsiveness.

View larger version (13K): [in this window] [in a new window]   Figure 4.   Single-breath nitrogen tests during and after a histamine challenge in a young patient with asthma with normal lung function and a normal distribution of ventilation (slope of phase III) and closing volume before the challenge. Fifteen minutes after the challenge, when the FEV1/FVC had fallen, there was severe maldistribution of ventilation. After bronchodilation (ABD), when lung function was normal, the slope of phase III remained increased. VC = vital capacity; V50 = flow at 50% VC.

Difficulties in Imaging the Airways

Bronchograms. Although bronchograms are no longer undertaken, they illustrate that large airways can narrow to closure in patients with asthma. Figure 5 is a bronchogram taken in 1938 (10) of an asthmatic who had an attack of asthma. The arrows indicate where the airway is blocked. Presumably, if this patient had inhaled some sort of medication it would not have gone past the narrow areas. There is evidence that this narrowing is not due to mucus and that after a bronchodilator is administered the airway filling improves.

View larger version (127K): [in this window] [in a new window]   Figure 5.   A bronchogram done in 1938 from Rigler and Koucky (10). The airways indicated by the arrows are blocked so that inhaled medications would not reach the small airways in these regions.

Radioactive labeling of drugs. Little has been known about the deposition of inhaled corticosteroids from current metered-dose inhalers until recently. Radiolabel studies in normal subjects where the association of drug and label were well validated have shown that most of the drug impacts in the oropharynx and a small proportion reaches the lungs, mainly in the large airways. In contrast, a new formulation of beclomethasone dipropionate solution in hydrofluoroalkane propellants (Figure 6) allows most of the drug to reach the lung, with a more uniform distribution through the lung fields (11).

View larger version (64K): [in this window] [in a new window]   Figure 6.   Comparative deposition patterns of (a) beclomethasone diproprionate in chlorinated fluorocarbon propellant and (b) beclomethasone diproprionate in hydrofluoroalkane propellants in healthy volunteers.

	FUTURE APPROACHES

Radioactive Labeling of Small Particles

Camner, Svartengren, and coworkers have studied the regional distribution of 3.6-µm particles and lung function in asthmatic subjects (12). Ten subjects inhaled radioactively labeled 3.6-µm Teflon particles suspended in air or in a helium-oxygen mixture. The particles went into the small airways, lodging further into the small airways when they were inhaled with the helium-oxygen mixture than with air. In another study, the tracheobronchial deposition and clearance in small airways of patients with mild asthma and normal subjects was monitored (13). This study showed that the 6-µm Teflon particles entered the small airways; unexpectedly, the clearance from them was not severely impaired in mild to moderate asthma. This group now has a method for depositing particles in the small airways, which provides a technique for future studies.

Single Photon Emission Computed Tomography Scanning

Peter Macklem has already discussed single photon emission computed tomography (SPECT) scanning and showed some work from King (14). A bolus of Technegas (300 ml) was inhaled during inspiration from residual volume (RV). Technegas is composed of technetium-labeled carbon particles so small that they behave like a gas. However, they adhere to the alveolar walls for at least 20 min, allowing simultaneous SPECT transmission and emission scans to be performed on the patients. The subject is upright when the technetium is inhaled and supine for the scanning, and a small correction is made for the change in lung volume on lying down. The transmission scan is from an external source that rotates around the patient and transmits radioactivity through the soft and hard tissues, imaging everything except the lung. At the same time, the emission scan from the inhaled technetium is collected. Computer manipulation, using segmentation and binarization, allows the location of the gas to be identified, thus defining areas of airway closure in vivo.

In asthmatic subjects there is more airway closure at residual volume than in normal subjects of the same age. After a methacholine challenge, there is even more airway closure (15). By subtracting the images, the areas of the lung that close during the methacholine challenge can be defined: usually large segments of lung appear to close. It could be argued that the lack of filling is due to closure of a large number of small airways, but it seems more likely that the defects result from closure at the level of the central airways. The filling defects from discrete patches rather than small areas all over the lung fields and cholinergic muscarinic receptors are densest within the central airways. King and colleagues have also compared airway closure after methacholine and hypertonic saline challenges on different days in asthmatic subjects. In general, the closure after hypertonic saline was more peripheral than the closure after methacholine challenges (15). In the future, SPECT scanning may prove to be a way of imaging the small airways in asthma.

	SUMMARY

TOP INTRODUCTION CONCLUSION REFERENCES

Little is known about the effects of drugs on small airways. However, the small airways respond to constricting and dilating substances in vitro. Pathologic assessment demonstrates that small airways are inflamed, and the physiology suggests that they narrow and dilate. If after a period of treatment for asthma, all tests including the SBNT are normal, it would be safe to say that the small airways had been treated. However, we need to have some way of imaging the airways to decide whether or not there is abnormality in the small airways and to target the drugs that we are using to treat them. New ways of imaging, measuring, and performing a biopsy of the small airways are needed if we are going to make progress in this area.

	Footnotes

Correspondence and requests for reprints should be addressed to Professor Ann J. Woolcock, Institute of Respiratory Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia.

	References

TOP INTRODUCTION CONCLUSION REFERENCES

1. Patel, P., D. Mukai, and A. F. Wilson. 1990. Dose-response effects of two sizes of monodispersed isoproterenol in mild athma. Am. Rev. Respir. Dis. 141: 357-360 [Medline].

2. Carroll, N., E. Lehmann, J. Barret, A. Morton, C. Cooke, and A. James. 1996. Variability of airway structure and inflammation in normal subjects and in cases of nonfatal and fatal asthma. Pathol. Res. Pract. 192: 238-248 [Medline].

3. Carroll, N., J. Elliot, A. Morton, and A. James. 1993. The structure of large and small airways in nonfatal and fatal asthma. Am. Rev. Respir. Dis. 147: 405-410 [Medline].

4. Carroll, N., S. Carello, C. Cooke, and A. James. 1996. Airway structure and inflammatory cells in fatal attacks of asthma. Eur. Respir. J. 9: 709-715 [Abstract].

5. Kuwano, K., C. H. Bosken, P. D. Pare, T. R. Bai, B. R. Wiggs, and J. C. Hogg. 1993. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 148: 1220-1225 [Medline].

6. Saetta, M., A. D. Stefano, C. Rosina, G. Thiene, and L. M. Fabbri. 1991. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. Am. Rev. Respir. Dis. 143: 138-143 [Medline].

7. Armour, C. L., J. L. Black, and N. Berend. 1985. The lung parenchymal strip as a model of peripheral airway responsiveness. Bull. Eur. Physiopathol. Respir. 21: 545-549 [Medline].

8. Stanescu, D., D. Teculexcu, and R. Pacuraru. 1968. Reproducibility and normal values of the single breath nitrogen test. Scand. J. Respir. Dis. 49: 322-330 [Medline].

9. Woolcock, A. J., S. R. Leeder, J. G. Armstrong, J. K. Peat, M. Colman, and K. J. Cullen. 1978. The single breath nitrogen test in rural and urban smokers and non-smokers. Bull. Eur. Physiopathol. Respir. 14: 127-135 [Medline].

10. Rigler, L. G., and R. Koucky. 1938. Roentgen studies of pathological physiology of bronchial asthma. Am. J. Roentgenol. 39: 353-362 .

11. Leach, C. 1996. Enhanced drug delivery through reformulating MDIs with HFA propellantsdrug deposition and its effect on preclinical and clinical programs. In R. N. Dalby, P. R. Byron, and S. J. Farr, editors. Respiratory Drug Delivery V Proceedings. Interpharm Press, Buffalo Grove, IL. 133-144.

12. Anderson, M., M. Svartengren, G. Bylin, K. Philipson, and P. Camner. 1993. Deposition in asthmatics of particles inhaled in air or in helium-oxygen. Am. Rev. Respir. Dis. 147: 524-528 [Medline].

13. Svartengren, M., C. H. Ericsson, K. Philipson, B. Mossberg, and P. Camner. 1989. Tracheobronchial clearance in asthma-discordant monozygotic twins. Respiration 56: 70-79 [Medline].

14. King, G. G., S. Eberl, C. M. Salome, S. R. Meikle, and A. J. Woolcock. 1997. Airway closure measured by a technegas bolus and SPECT. Am. J. Respir. Crit. Care Med. 155: 682-688 [Abstract].

15. King, G. G., S. Eberl, C. M. Salome, and A. J. Woolcock. 1997. Hypertonic saline challenge causes less airway closure than methacholine challenge (abstract). Am. J. Respir. Crit. Care Med. 155: A679 .