The Phosphodiesterase Type IV Inhibitor Cilomilast Decreases Pro-inflammatory Cytokine Production From Primary Bronchial Epithelial Cells in Lung Transplantation Patients

Abstract

Bronchiolitis obliterans syndrome (BOS) remains the major cause of long-term morbidity and mortality after lung transplantation, and new therapeutic measures are needed. We speculated that cilomilast might reduce mediators of airway inflammation and angiogenesis from the airway epithelium, supporting a potential value in the treatment of BOS. We used an ex vivo primary bronchial epithelial cell culture (PBEC) model to investigate this hypothesis. Increasing evidence suggests the epithelium is central in stimulating both inflammatory and proliferative responses in the airway. Bronchial brushings were taken from 7 stable lung allograft recipients and were used to establish sub-confluent PBECs. The effect of incubation for 48 hours with 0.1 to 10 micromol/liter cilomilast on basal production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor (GMCSF), and vascular endothelial growth factor (VEGF) were assayed by multiplex analyser. There was a dose dependent fall in basal IL-8 and GMCSF levels with cilomilast. Median change for IL-8 was -25% (range, -66% to 5%; p = 0.035) at 1 micromol/liter , and -40% (range, -72% to -20; p = 0.022) at 10 micromol/liter. Median GMSCF change was -34% (range, -70% to 16%; p = 0.05) at 1 micromol/liter, and 37% (range, -80% to -8%; p = 0.04) at 10 micromol/liter. There were no effects on VEGF. The phosphodiesterase type IV inhibitor cilomilast reduced IL-8 and GMCSF release from PBECs. These cytokines are associated with the persistence of airway neutrophilic inflammation and airway remodelling seen in obliterative bronchiolitis. These ex vivo results suggest a potential for cilomilast in the treatment of BOS, which would need to be evaluated in appropriate clinical studies.