Cellular Hypertrophy and Hyperplasia of Airway Smooth Muscles Underlying Bronchial Asthma: A 3-D Morphometric Study

Abstract

In order to study whether hyperplasia or hypertrophy of cells is responsible for the thickening of airway muscles, 3-D morphometry of airway muscle cells was performed on resin-embedded semithin serial sections of autopsied lungs from 10 asthmatics and five control subjects. There were five Type I and five Type II asthmatic lungs, as defined in an earlier study, thickened muscles being found only in the central bronchi in Type I and distributed over the whole airway tree in Type II. The analysis was based on "unbiased" 3-D morphometry to obtain the numerical density NV of muscle cells using a "disector," a spatial probe introduced by Sterio in 1984, which we modified into a stack of serial sections. The mean number NL of cells per unit airway length and the mean volume Vc of a single muscle cell were also determined. In Type I asthmatics, the number of cells increased in the larger bronchi unaccompanied by cellular hypertrophy at any level of the airway tree. In contrast, in Type II asthmatics, hypertrophy was shown to prevail over the whole airway, but it was most remarkable in the bronchioles, whereas hyperplasia was mild and localized only in the bronchi. The two types of asthmatic lungs may therefore result from different pathogeneses.

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

“…In studies in which the contribution of cellular hyperplasia and hypertrophy to the increased airway smooth muscle content have been investigated using this model, the number of smooth muscle cell nuclei undergoing S-phase traversal (a surrogate for proliferation), determined in vivo by labelling with the thymidine analogue, bromodeoxyuridine (BrdU), was found to be increased only in large-and medium-sized airways, being absent in the smaller airways [44]. The observed increase in smooth muscle content was also limited to large and medium airways, which, together with the pattern of DNA synthesis, is perhaps reminiscent of the type I thickening reported earlier by EBINA et al [11] in a subset of patients with fatal asthma. Although the precise mechanisms that induce DNA synthesis in airway smooth muscle cells in vivo remain unknown, a leukotriene (LT) D 4 receptor antagonist, MK-571, has been shown to partially prevent the increase in airway smooth muscle content in the Brown Norway rat following repeated allergen exposure [43].…”

“…Although other components of airway wall remodelling may also be important in determining airways hyperresponsiveness (e.g. increased mucosal thickness and increased adventitial thickening), this study [11], as well as that of HEARD and HOSSAIN [6], forms the basis of the current belief that the major smooth muscle abnormality that contributes to the development of airway wall thickening in chronic severe asthma involves excessive muscle hyperplasia and hypertrophy. Accordingly, investigators are now addressing the cellular and molecular mechanisms which drive the increase in muscle in this tissue, although, to an extent, this has been at the expense of investigating other aberrant responses of smooth muscle such as increased cell survival or deposition of extracellular matrix proteins within the myobundles [12].…”

“…In order to resolve this, EBINA et al [10], using sophisticated three-dimensional morphometry, mapped these changes in both large and small airways and found that, in asthmatic subjects, airway wall thickening was present throughout the entire range of the bronchial tree including the smaller airways. In a subsequent study, these authors investigated the mechanism of muscular thickening and reported at least two patterns of smooth muscle thickening in the lungs of patients with fatal asthma, described as types I and II [11]. In the type I subgroup, smooth muscle cell hyperplasia was responsible for airway smooth muscle thickening in the large central airways.…”

“…Because of the difficulties in obtaining airway smooth muscle from normal or asthmatic subjects, the significance of this heterogeneity in the intact human airway has not been evaluated. It may be important in determining nonhomogeneous bronchoconstriction [10,25] or hyperplasia and hypertrophy [11] of airway smooth muscle, and has led to speculation that, in airways of individuals with chronic severe asthma, the extent of this heterogeneity may be increased, subtly altering the properties of the tissue [26,27]. This, in turn, could offer prospects for the development of future therapeutic strategies targeting the smaller airways of the lung.…”

Allergen‐induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N‐terminal kinase

“…One of the consequences of chronic airway inflammation in asthma is remodelling of the airways, which consists of increases in airway smooth muscle (ASM) mass (Dunnill et al, 1969), goblet cell hyperplasia (Laitinen et al, 1985;Aikawa, 2001) and subepithelial fibrosis (Roche et al, 1989). ASM thickening in chronic asthma involves both hyperplasia and hypertrophy of ASM cells (Ebina et al, 1993) and compared with other structural abnormalities in the airways of asthmatics, increased ASM mass is a most important determinant of excessive airway lumen narrowing (James et al, 1989). The mechanisms underlying these ASM changes are complex, involving proinflammatory and mitogenic cytokines and growth factors.…”