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

Abstract

Background and objective: 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. Methods: Post-mortem cases of asthma (n = 68) were categorized by the distribution of increased thickness of the ASM layer (relative to nonasthmatic controls, n = 37), into 'large only' (LO, n = 15), 'small only' (SO, n = 4) 'large/small' (LS, n = 24) or no increase (NI, n = 25). Subject characteristics, ASM and airway wall dimensions and inflammatory cell numbers were compared between groups. Results: Apart from reduced clinical severity of asthma in NI cases (P = 0.002), subject characteristics did not distinguish asthma groups. Compared with control subjects, ASM cell number, reticular basement membrane thickness, airway wall thickness, percent muscle shortening and eosinophil number were increased (P < 0.05) in both large and small airways in LS cases and only the large airways in LO cases. Increased numbers of neutrophils were observed only in the small airways of LO cases. Conclusions: Distinct distributions of ASM remodelling are seen in asthma. Pathology limited to the small airways was uncommon. Increased thickness of the ASM layer was associated with airway remodelling and eosinophilia, but not neutrophilia. These data support the presence of distinct pathological phenotypes based on the site of increased ASM.

Novel concepts in airway inflammation and remodelling in asthma

“…Another study in smokers with severe asthma has shown a relationship between low sputum MMP-9/TIMP (tissue inhibitors of metalloproteinase) ratio, persistent airflow obstruction and reduced airway lumen on CT [57]. However, a post mortem study of fatal asthma patients showed increased smooth muscle was only associated with airway eosinophilia, but not neutrophilia [58]. It is therefore apparent that more assessments of airway structure and mechanistic studies are needed to better understand the relationship between neutrophils, MMP-9, lung function and remodelling, especially if MMP-9 might be a potential therapeutic target for neutrophil predominant disease.…”

‘To measure is to know’ (Lord Kelvin)

“…6 This creates a paradox with the findings of the present study of post-mortem lung, which indicated that there were no differences in neutrophil density in the large airways between asthma and controls. 3 The current study also points out that airway smooth muscle remodelling, a central tenet of the modern asthma paradigm, was not present in 37% of cases, commonly but not exclusively, in the mild to moderate asthmatics.…”

“…3 Airway smooth muscle thickening was associated with eosinophilia but not neutrophilia, and there were no significant differences in neutrophil density in the large airways of the 68 asthmatics compared with 37 controls studied, a considerable body of work. 3 This observation underscores the concept that neutrophilic inflammation in asthma may be very hard to determine. It is also likely that in vivo both cell counts and cellular activity will be important in pathophysiology.…”

“…2,3 This approach, albeit with inherent limitations, can combine descriptive but powerful information on both inflammatory and structural differences in asthmatics.…”

Gene expression in asthmatic airway smooth muscle: a mixed bag

“…However, to date there has been no consensus on whether phenotypic differences in the ASM of asthmatics contributes to AHR (Gunst et al 2012;Paré and Mitzner 2012). While there is general agreement that there is a greater amount of ASM in mild/moderate, and especially in severe, asthma (Dunnill et al 1969;Ebina et al 1993;Woodruff et al 2004;Chin et al 2012;James et al 2012;Elliot et al 2014), it is unclear whether the hyperplastic/hypertrophied ASM behaves differently due to altered expression of genes for contractile, cytoskeletal, or inflammatory function.…”