Can airways close completely?

The following is the abstract of the article discussed in the subsequent letter:

	ABSTRACT

Seow, Chun Y., Lu Wang, and Peter D. Paré.

Airway narrowing and internal structural constraints. J. Appl. Physiol. 88: 527-533, 2000.A computer model has been developed to simulate the movement restriction in the lamina propria-submucosa (L-S) layer (sandwiched by the basement membrane and the muscle layer) in a cartilage-free airway due to constriction of the smooth muscle layer. It is assumed that the basement membrane is inextensible; therefore, in the two-dimensional simulation, the perimeter outlining the membrane is a constant whether the airway is constricted or dilated. The cross-sectional area of the L-S layer is also assumed to be constant during the simulated airway narrowing. Folding of the mucosal membrane in constricted airways is assumed to be a consequence of the L-S area conservation and also due to tethering between the basement membrane and the muscle layer. The number of tethers determines the number of folds. The simulation indicates that the pressure in the L-S layer resulting from movement restriction can be a major force opposing muscle contraction and that the maximum shortening of the muscle layer is inversely proportional to the number of tethers (or folds) and the L-S layer thickness.

	LETTER

Can airways close completely?

To the Editor: The manuscript by Dr. Seow and colleagues (3) presents some very interesting considerations concerning the nature and the extent of airway contraction. Our comment does not address the principal message of their work; rather, it addresses one of their assumptions. They assume that airway constriction is never complete; i.e. "even in very constricted bronchi, the mucosal membranes on opposite sides of the lumen do not touch." According to our own experience, we wonder whether this is true under all circumstances.

We have found at least three pieces of evidence that demonstrate complete closure of airways. First, the model of precision-cut lung slices (PCLSs) allows the observation of live airways under the microscope (2). Thus, in contrast to conventional histology, in which an airway may have already relaxed to some extent when the lung is prepared, with PCLSs the time course of the contraction can be followed in the same single airway. In such experiments, we frequently observe that airways do completely close (see Fig. 1). Second, we have previously seen complete airway closure in isolated rat lungs perfused with the thromboxane mimetic U-46619. Figure 2 shows a light microscopic picture of an airway from such a lung in which the mucosal membranes on opposite sides of the lumen do touch; a scanning electron microscope picture from such lungs was presented in Ref. 5. Third, complete closure of airways has also been demonstrated by bronchoscopic video imaging in human asthmatic patients after segmental allergen provocation (1). It should also be noted that sometimes complete closure of airways may be prevented by the presence of mucus within the airways, as exemplified by some of the micrographs shown in Ref. 4.

View larger version (67K): [in this window] [in a new window]   Fig. 1.   Bronchoconstriction induced by methacholine in precision-cut rat lung slices. Viable slices were placed under the microscope and incubated with 100 µM methacholine. Shown is the same airway before (A) and after (B) addition of methacholine.

View larger version (77K): [in this window] [in a new window]   Fig. 2.   Bronchoconstriction induced by the thromboxane/prostanoid-receptor agonist U-46619 in the isolated perfused rat lung. Ten minutes after treatment with 5 nmol U-46619, lungs were fixed by perfusing the pulmonary artery with 1.5% glutaraldehyde-1.5% paraformaldehyde in 0.2 M HEPES buffer (pH 7.4) at a hydrostatic pressure of 13 cmH2O. The lungs were stored in cold fixative for 24 h. For further methodological details, see Refs. 4 and 5. The micrograph shows a completely closed airway on the right and an open vessel on the left.

Taken together, there is both experimental and clinical evidence that airways can completely close.

	REFERENCES

1.   Krug, N, Teran LM, Redington AE, Gratziou C, Montefort S, Polosa R, Brewster H, Howarth PH, Holgate ST, Frew AJ, and Carroll MP. Safety aspects of local endobronchial allergen challenge in asthmatic patients. Am J Respir Crit Care Med 153: 1391-1397, 1996[Abstract].

2.   Martin, C., Uhlig S, and Ullrich V. Videomicroscopy of methacholine-induced contraction of individual airways in precision-cut lung slices. Eur Respir J 9: 2479-2487, 1996[Abstract].

3.   Seow, CY, Wang L, and Paré PD. Airway narrowing and internal structural constraints. J Appl Physiol 88: 527-533, 2000[Abstract/Free Full Text].

4.   Uhlig, S, Brasch F, Wollin L, Fehrenbach H, Richter J, and Wendel A. Functional and fine structural changes in isolated lungs challenged with endotoxin ex vivo and in vitro. Am J Pathol 146: 1235-1247, 1995[Abstract].

5.   Uhlig, S, Nüsing R, von Bethmann A, Featherstone RL, Klein T, Brasch F, Müller K-M, Ullrich V, and Wendel A. Cyclooxygenase-2 dependent bronchoconstriction in perfused rat lungs exposed to endotoxin. Mol Med 2: 373-383, 1996[ISI][Medline].

					Stefan Uhlig, Andrea Wohlsen, Division Pulmonary Pharmacology Research Center Borstel 23845 Borstel, Germany
					Frank Brasch, Institute of Pathology Professional Associations Bergmannsheil University Hospital 44789 Bochum, Germany

	REPLY

To the Editor: As Dr. Uhlig and colleagues point out, we overstated the case by saying that "even in very constricted bronchi, the mucosal membranes on opposite sides of the lumen do not touch." Dr. Uhlig and his colleagues have presented convincing evidence that some airways can completely close during bronchoconstriction. In addition, Brown and Mitzner. (1) have recently demonstrated complete closure of central airways in dogs using high-resolution computerized tomography scanning. Clearly, under some circumstances, some airways are thus capable of closure. An important question remains: Why do not all airways close during bronchoconstriction, since the airway smooth muscle's capacity to shorten is sufficient to close all airways (2)? The most likely explanation is that there are elastic loads that impede the ability of airway smooth muscle to shorten maximally; these loads are related to the static and cyclic elastic recoil of the surrounding lung parenchyma (3), the folding of the mucosal membrane (4, 5), and, as we suggested in our model (6), the tethering provided by radial collagen-elastin fibers. It is the dynamic balance between the muscle's ability to generate force and these loads that determines the degree of airway narrowing. The fact that some airways are capable of complete closure indicates that, under some circumstances, these loads are insufficient to attenuate airway smooth muscle shortening.

	REFERENCES

1.   Brown, RH, and Mitzner W. The myth of maximal airway responsiveness in vivo. J Appl Physiol 85: 2012-2017, 1998[Abstract/Free Full Text].

2.   Macklem, PT. Bronchial hyporesponsiveness. Chest 91, Suppl 6: 189S-191S, 1987[Abstract].

3.   Lambert, RK, Wiggs BR, Kuwano K, Hogg JC, and Paré PD. Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol. 74: 2771-2781, 1993[Abstract/Free Full Text].

4.   Lambert, RK, Codd SL, Alley MR, and Pack RJ. Physical determinants of bronchial mucosal folding. J Appl Physiol 77: 1206-1216, 1994[Abstract/Free Full Text].

5.   Wiggs, BR, Hrousis CA, Drazen JM, and Kamm RD. On the mechanism of mucosal folding in normal and asthmatic airways. J Appl Physiol. 199783: 1814-1821, 1997.

6.   Seow, CY, Wang L, and Paré PD. Airway narrowing and internal structural constraints. J Appl Physiol 88: 527-533, 2000.

					Chun Y. Seow, Department of Pharmacology and Therapeutics University of British Columbia Vancouver, British Columbia, Canada V6T 1Z3
					Peter D. Paré, Pulmonary Research Laboratory St. Paul's Hospital University of British Columbia Vancouver, British Columbia, Canada V6Z 1Y6