Functional KCa3.1 K+ channels are required for human fibrocyte migration

Background: Fibrocytes are bone marrow-derived CD34(+) collagen I-positive cells present in peripheral blood that develop alpha-smooth muscle actin expression and contractile activity in tissue culture. They are implicated in the pathogenesis of tissue remodeling and fibrosis in both patients with asthma and those with idiopathic pulmonary fibrosis. Targeting fibrocyte migration might therefore offer a new approach for the treatment of these diseases. Ion channels play key roles in cell function, but the ion-channel repertoire of human fibrocytes is unknown. Objective: We sought to examine whether human fibrocytes express the K(Ca)3.1 K+ channel and to determine its role in cell differentiation, survival, and migration. Methods: Fibrocytes were cultured from the peripheral blood of healthy subjects and patients with asthma. Whole-cell patch-lamp electrophysiology was used for the measurement of ion currents, whereas mRNA and protein were examined to confirm channel expression. Fibrocyte migration and proliferation assays were performed in the presence of K(Ca)3.1 ion-channel blockers. Results: Human fibrocytes cultured from the peripheral blood of both healthy control subjects and asthmatic patients expressed robust K(Ca)3.1 ion currents together with K(Ca)3.1 mRNA and protein. Two specific and distinct K(Ca)3.1 blockers (TRAM-34 and ICA-17043) markedly inhibited fibrocyte migration in transwell migration assays. Channel blockers had no effect on fibrocyte growth, apoptosis, or differentiation in cell culture. Conclusions: The K+ channel K(Ca)3.1 plays a key role in human fibrocyte migration. Currently available K(Ca)3.1-channel blockers might therefore attenuate tissue fibrosis and remodeling in patients with diseases such as idiopathic pulmonary fibrosis and asthma through the inhibition of fibrocyte recruitment. (J Allergy Clin Immunol 2011;128:1303-9.)