Robyn L. Jones

Airway Smooth Muscle Hypertrophy and Hyperplasia in Asthma

RATIONALE Increased thickness of the airway smooth muscle (ASM) layer in asthma may result from hyperplasia or hypertrophy of muscle cells or increased extracellular matrix (ECM). OBJECTIVES To relate ASM hypertrophy, ASM hyperplasia, and deposition of ECM to the severity and duration of asthma. METHODS Airways from control subjects (n = 51) and from cases of nonfatal (n = 49) and fatal (n = 55) asthma were examined postmortem. Mean ASM cell volume (V(C)), the number of ASM cells per length of airway (N(L)), and the volume fraction of extracellular matrix (f(ECM)) within the ASM layer were estimated. Comparisons between subject groups were made on the basis of general linear regression models. MEASUREMENTS AND MAIN RESULTS Mean V(C) was increased in the large airways of cases of nonfatal asthma (P = 0.015) and fatal asthma (P < 0.001) compared with control subjects. N(L) was similar in nonfatal cases and control subjects but increased in large (P < 0.001), medium (P < 0.001), and small (P = 0.034) airways of cases of fatal asthma compared with control subjects and with nonfatal cases (large and medium airways, P ≤ 0.003). The f(ECM) was similar in cases of asthma and control subjects. Duration of asthma was associated with a small increase in N(L). CONCLUSIONS Hypertrophy of ASM cells occurs in the large airways in both nonfatal and fatal cases of asthma, but hyperplasia of ASM cells is present in the large and small airways in fatal asthma cases only. Both are associated with an absolute increase in ECM. Duration of asthma has little or no effect on ASM hypertrophy or hyperplasia or f(ECM).

Airway narrowing and bronchodilation to deep inspiration in bronchial segments from subjects with and without reported asthma.

The present study presents preliminary findings on how structural/functional abnormalities of the airway wall relate to excessive airway narrowing and reduced bronchodilatory response to deep inspiration (DI) in subjects with a history of asthma. Bronchial segments were acquired from subjects undergoing surgery, mostly to remove pulmonary neoplasms. Subjects reported prior doctor-diagnosed asthma (n = 5) or had no history of asthma (n = 8). In vitro airway narrowing in response to acetylcholine was assessed to determine maximal bronchoconstriction and sensitivity, under static conditions and during simulated tidal and DI maneuvers. Fixed airway segments were sectioned for measurement of airway wall dimensions, particularly the airway smooth muscle (ASM) layer. Airways from subjects with a history of asthma had increased ASM (P = 0.014), greater maximal airway narrowing under static conditions (P = 0.003), but no change in sensitivity. Maximal airway narrowing was positively correlated with the area of the ASM layer (r = 0.58, P = 0.039). In tidally oscillating airways, DI produced bronchodilation in airways from the control group (P = 0.0001) and the group with a history of asthma (P = 0.001). While bronchodilation to DI was reduced with increased airway narrowing (P = 0.02; r = -0.64)), when the level of airway narrowing was matched, there was no difference in magnitude of bronchodilation to DI between groups. Results suggest that greater ASM mass in asthma contributes to exaggerated airway narrowing in vivo. In comparison, the airway wall in asthma may have a normal response to mechanical stretch during DI. We propose that increased maximal airway narrowing and the reduced bronchodilatory response to DI in asthma are independent.

Distribution of airway smooth muscle remodelling in asthma: Relation to airway inflammation

Pathological phenotypes of asthma have been based predominantly on inflammation, rather than airway wall remodelling. Differences in the distribution of airway smooth muscle (ASM) remodelling between large and small airways may affect clinical outcomes in asthma. The aim of this study was to examine the distribution of ASM remodelling and its relation to airway inflammation.

Airway remodelling in COPD: It's not asthma!

COPD is defined as airflow limitation that is not reversed by treatment. In asthma, airflow limitation is not only reversible, but also inducible. This is called ‘airway hyperresponsiveness’ (AHR) and is associated with thickening of the airway wall, predominantly the layer of airway smooth muscle, due to more cells, bigger cells and more extracellular matrix (ECM) in proportion to the increase in smooth muscle. AHR is also observed in COPD if the changes in airflow are expressed as a percent of the baseline lung function. However, the absolute change in baseline lung function that can be induced in COPD is actually less than that seen in normal subjects, suggesting that the airways in COPD are resistant not only to opening, but also to closing. This observation agrees with physiological measures showing increased airway wall stiffness in COPD. Like asthma, airway wall thickness is increased in COPD, including the layer of smooth muscle. Unlike asthma, however, fixed airflow obstruction appears to be characterized by a disproportionate increase in the ECM within the smooth muscle layer. In this review, we summarize the studies of airway matrix deposition in COPD and put forward the proposal that the airway remodelling in COPD is different from that in asthma and call for a systematic analysis of airway matrix deposition in COPD.

Estimating Airway Smooth Muscle Cell Volume and Number in Airway Sections. Sources of Variability

Hypertrophy and hyperplasia of airway smooth muscle (ASM) cells are features of asthma that can be assessed in airway transverse sections using stereologically derived parameters. However, little is known about the variability of these parameters within and between airways. The aim of the present study was to assess sources of variation in the measurement of the area of the ASM layer (AASM), and the volume fraction of ASM cells (VVASM) and numerical density of ASM cells within that layer. AASM increased by up to 12% in 4-μm sections, and 28% in 30-μm sections, compared with 0.5-μm sections. AASM was greater (P < 0.05) in large than in small airways, and varied by up to 28% along segments of large airways. Numerical density of ASM cell estimates around the airway circumference varied by less than 10% if 40 random high-power fields were sampled. VVASM was most accurately estimated on 0.5-μm, rather than 4- or 30-μm sections, and was less (P < 0.05) in large than in small airways. The coefficients of variation for VVASM were less than 10% along airway segments. We found that variation of parameters used to estimate ASM cell number or size could be minimized with adequate sampling frequency around or along airway segments. Section thickness was positively related to the measured area of ASM on transverse airway sections. Thin (0.5-μm) sections should be used to estimate tissue volume fractions, which vary little within and between airways of similar size. Airway size contributes most to the variation in estimating parameters of the ASM layer.

Airflow obstruction is associated with increased smooth muscle extracellular matrix

Increased thickness of the airway smooth muscle (ASM) layer is a characteristic feature of airway remodelling in both asthma and chronic obstructive pulmonary disease (COPD) [1, 2]. The composition of the ASM layer has been well studied in asthma where the increased thickness of the ASM layer is due to hypertrophy and/or hyperplasia [3–5] of ASM cells. These changes are associated with a concomitant increase in absolute volumes of both ASM and extracellular matrix (ECM), without changes in their relative volume fractions [5]. Although ASM cell hypertrophy has been reported in the large airways of patients with COPD [6], these findings did not exclude the effect of an increase in the volume fraction of ECM on the estimated average volume of the ASM cells [7]. Remodelling of the layer of airway smooth muscle in COPD is characterised by an increase in the extracellular matrix http://ow.ly/YZqhz