Airway basement membrane perimeter in human airways is not a constant; potential implications for airway remodeling in asthma

Abstract

Many studies that demonstrate an increase in airway smooth muscle in asthmatic patients rely on the assumption that bronchial internal perimeter (P(i)) or basement membrane perimeter (P(bm)) is a constant, i.e., not affected by fixation pressure or the degree of smooth muscle shortening. Because it is the basement membrane that has been purported to be the indistensible structure, this study examines the assumption that P(bm) is not affected by fixation pressure. P(bm) was determined for the same human airway segment (n = 12) fixed at distending pressures of 0 cmH(2)O and 21 cmH(2)O in the absence of smooth muscle tone. P(bm) for the segment fixed at 0 cmH(2)O was determined morphometrically, and the P(bm) for the same segment, had the segment been fixed at 21 cmH(2)O, was predicted from knowing the luminal volume and length of the airway when distended to 21 cmH(2)O (organ bath-derived P(i)). To ensure an accurate transformation of the organ bath-derived P(i) value to a morphometry-derived P(bm) value, had the segment been fixed at 21 cmH(2)O, the relationship between organ bath-derived P(i) and morphometry-derived P(bm) was determined for five different bronchial segments distended to 21 cmH(2)O and fixed at 21 cmH(2)O (r(2) = 0.99, P < 0.0001). Mean P(bm) for bronchial segments fixed at 0 cmH(2)O was 9.4 +/- 0.4 mm, whereas mean predicted P(bm), had the segments been fixed at 21 cmH(2)O, was 14.1 +/- 0.5 mm (P < 0.0001). This indicates that P(bm) is not a constant when isolated airway segments without smooth muscle tone are fixed distended to 21 cmH(2)O. The implication of these results is that the increase in smooth muscle mass in asthma may have been overestimated in some previous studies. Therefore, further studies are required to examine the potential artifact using whole lungs with and without abolition of airway smooth muscle tone and/or inflation.

Elastic properties of the bronchial mucosa: epithelial unfolding and stretch in response to airway inflation

“…Bronchi were taken from animals of the same body weight and at the same anatomic location and had the same luminal diameter at 0 cmH 2 O as measured by gentle insertion of steel rods of known diameter into the distal and proximal ends of the lumen. Results showed that, at 5-25 cmH 2 O luminal pressure, P i increased by 25%, which is less than that recently reported by McParland et al (7) in human airway segments. For comparison with mucosal strips, the difference in epithelial length was measured from the inflationary strains associated with 5 and 25 cmH 2 O luminal pressure in an airway by interpolation of the relation between strain and epithelial length shown in Fig.…”

“…Previous studies provided conflicting data on the capacity of the epithelium to distend (as opposed to unfold) (4). However, a recent study suggested that the basement membrane has the capacity to stretch at physiological pressures (7). Previous and present findings provide strong evidence that the epithelium is distensible at physiological pressures, and we suggest that normalization of airway size by the luminal perimeter is not a reliable approach, particularly where airways are examined after different lung fixation pressures.…”

“…However, other studies suggest that the epithelium may be distensible over physiologically relevant pressures. In human bronchial segments, McParland et al (7) found evidence that the epithelium distends as much as 50% when airways are inflated to total lung capacity (TLC).…”

Development and characterization of a 3D multicell microtissue culture model of airway smooth muscle

“…In any case, our results indicate that there was a high level of active tension attributable to actinomyosin crossbridge cycling even at baseline, as well as significant passive cytoskeletal stiffness. Similar intrinsic ASM tone has been observed under many circumstances including ex vivo human airway segments (46,51) and in 2D cultures (2,34). This may provide a benefit for microtissues over ex vivo ASM strips, which tend to have far less active tension than airway segments (37) and do not show relaxation responses unless previously activated with a contractile agonist.…”

Chronic Effects of Mechanical Force on Airways

“…Until recently it had been widely assumed that the basement membrane underlying the epithelium behaved as an inextensible membrane (laterally flexible, but rigid in compression and tension-similar to a bicycle chain) (98); the necessary corollary to this assumption is that changes in airway lumen dimensions (60) must be accommodated by folding and unfolding of the epithelial lining, not by lateral stretching or compression of the epithelium. Although the folding of the airway wall is a well-recognized phenomenon (99), recent evidence has called into question the assumption that the epithelial basement membrane is inextensible (100). Even in the presence of a minimally extensible basement membrane, bending of the epithelium and its substrate gives rise to local shear deformations and pressure gradients (9).…”