Reduced suppressive effect of β₂-adrenoceptor agonist on fibrocyte function in severe asthma

Background: 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). We determined the effect of β₂-AR agonists, alone or in combination with corticosteroids, on fibrocyte function. Methods: Non-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. Results: Salmeterol 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. Conclusions: Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.