Effect of roflumilast, novel phosphodiesterase-4 inhibitor, on lung chronic graft-versus-host disease in mice

Chronic graft-versus-host disease (CGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Roflumilast has anti-inflammatory effects and has been used in the treatment of inflammatory airway diseases. It is at present unclear whether roflumilast may have a therapeutic role in CGVHD. To test this, we used the B10.D2 → BALB/c model of CGVHD to address the therapeutic effect of roflumilast on the development of CGVHD. Lungs of animals treated with roflumilast exhibited less chronic inflammatory cell infiltration and fibrosis in the peribronchial and perivascular area versus allogeneic controls. To define the mechanism, we examined the expression of pro-inflammatory and profibrotic cytokines in the lung. Messenger RNA expression of interleukin-6 and interleukin-1β in the lungs was significantly reduced in recipients treated with roflumilast. Similar changes were observed in profibrotic cytokines and chemokines. In addition, the percentage of Foxp3⁺ regulatory T cells (Tregs), which have the potential to attenuate GVHD, increased significantly within the CD4⁺ T cells with roflumilast in the lungs. In conclusion, roflumilast treatment attenuated murine lung CGVHD by blocking T-cell activation mediated by Tregs and downregulating pro-inflammatory and profibrotic cytokines, resulting in the reduction of lung inflammation and fibrosis.