Gene expression in asthmatic airway smooth muscle: a mixed bag

Abstract

It has long been known that airway smooth muscle (ASM) contraction contributes significantly to the reversible airflow obstruction that defines asthma. It has also been postulated that phenotypic changes in ASM contribute to the airway hyperresponsiveness (AHR) that is a characteristic feature of asthma. Although there is agreement that the mass of ASM surrounding the airways is significantly increased in asthmatic compared with non-asthmatic airways, it is still uncertain whether there are quantitative or qualitative changes in the level of expression of the genes and proteins involved in the canonical contractile pathway in ASM that could account for AHR. This review will summarize past attempts at quantifying gene expression changes in the ASM of asthmatic lungs as well as non-asthmatic ASM cells stimulated with various inflammatory cytokines. The lack of consistent findings in asthmatic samples coupled with the relative concordance of results from stimulated ASM cells suggests that changes to the contractility of ASM tissues in asthma may be dependent on the presence of an inflammatory environment surrounding the ASM layer. Removal of the ASM from this environment could explain why hypercontractility is rarely seen ex vivo.Key words: asthma, airway smooth muscle, gene expression, protein expression, cytokines. Résumé :On sait depuis longtemps que la contraction du muscle lisse respiratoire (MLR) contribue de manière significative à l'obstruction réversible du débit d'air qui définit l'asthme. Il a aussi été postulé que des changements phénotypiques dans le MLR contribue à l'hyperréactivité bronchique (HRB) qui caractérise l'asthme. Même si l'on s'accorde sur le fait que la masse de MLR qui entoure les voies respiratoires est significativement plus importante en situation d'asthme comparativement à l'absence d'asthme, on ne sait pas encore avec certitude si des changements quantitatifs ou qualitatifs du niveau d'expression de gènes et de protéines impliqués dans les voies standards de régulation de la contraction chez le MLR pourraient expliquer l'HRB. Cet article de revue résumera les tentatives passées de quantification de changements d'expression génique dans des cellules de MLR de poumons asthmatiques et non asthmatiques, stimulées à l'aide de différentes cytokines inflammatoires. L'absence de données cohérentes issues d'échantillons asthmatiques, couplée à la concordance relative des résultats obtenus à partir de cellules de MLR stimulées suggère que les changements de contractilité du MLR dans l'asthme peuvent être dépendants de la présence d'un environnement inflammatoire autour de la couche de MLR. Le fait de retirer le MLR de son environnement pourrait expliquer pourquoi l'hyper-contractilité est rarement observée ex vivo. [Traduit par la Rédaction] Mots-clés : asthme, muscle lisse respiratoire, expression génique, expression protéique, cytokines.

CF airway smooth muscle transcriptome reveals a role for PYK2

“…Previous studies have identified transcriptional changes related to airway hyperresponsiveness (14)(15)(16). However, cell types other than smooth muscle (e.g., immune and epithelial cells) may have driven both transcriptional changes and airway hyperresponsiveness in these prior studies.…”

Beclomethasone dipropionate and formoterol fumarate synergistically interact in hyperresponsive medium bronchi and small airways

“…Surprisingly, in passively sensitized small airways, even very small total concentrations of BDP/FF combination, ranging between 1.06 ng/ml and 10.6 ng/ml, were effective in producing a marked synergistic relaxation of ASM. Certainly the increased acute bronchorelaxant effect of FF in isolated airways incubated overnight with BDP can be prevalently due to the genomic effect of the corticosteroid [ 61 , 62 ], although investigating this matter was beyond the scope of our study.…”

“…Furthermore, the functional impact of combining a corticosteroid with a β 2 -ARs was indirectly assessed by using cytosolic surrogate of ASM contractility [ 86 ]. In any case, even assuming that an ICS/LABA combination can modulate the expression of genes and proteins in asthmatic ASM, it is not implicit that such an interaction may lead to functional synergy [ 62 ]. Therefore, at the best of our knowledge, the present study provides for the first time the evidence-based pharmacological characterization of the synergism between an ICS and a LABA, at least with regard to the beneficial impact against BHR in human airways.…”

IL‐23 plays a significant role in the augmentation of particulate matter‐mediated allergic airway inflammation

“…As one of the mechanisms for the increase in airway hyperresponsiveness, we tried to confirm the change in the expression of α‐SMA. 17 To evaluate this, we performed IHC staining in lung tissues and found that the expression of α‐SMA around the airways was increased when PM and low‐dose Dp were administered, whereas it was decreased when anti‐IL‐23 antibody was administered (Figure 2I,J ).…”