Abstract
BackgroundPatients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.MethodsNon-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of β2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.ResultsSalmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.ConclusionsFibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.
Highlights
Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs)
Asthmatic inflammation is characterised by extensive airway remodelling involving sub-epithelial fibrosis and thickening of the airway smooth muscle (ASM) layer [1]. 5–10% of asthmatic patients suffer from severe asthma, which is difficult to control despite receiving high-dose inhaled corticosteroids and long-acting β2-adrenoceptor
There was an higher percentage of differentiated (α–smooth muscle actin (SMA)+) fibrocytes in the severe asthma group compared to non-severe asthma patients and healthy subjects (Additional file 2: Figure S3B) confirming our previous observations [8]
Summary
Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). Asthmatic inflammation is characterised by extensive airway remodelling involving sub-epithelial fibrosis and thickening of the airway smooth muscle (ASM) layer [1]. 5–10% of asthmatic patients suffer from severe asthma, which is difficult to control despite receiving high-dose inhaled corticosteroids and long-acting β2-adrenoceptor (β2-AR) agonists (LABA), leukotriene modifiers or theophylline [2]. There is more prominent sub-epithelial fibrosis and ASM thickening which contribute to airway obstruction [3]. Migration of fibrocytes towards allergen-exposed airways and their subsequent differentiation into α–smooth muscle actin (SMA)-expressing myofibroblasts may contribute to increased ASM mass and sub-epithelial fibrosis [5].
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