Targeting IL‐11 to reduce fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension‐associated lung fibrosis

Background and Purpose IL‐11 is a member of the IL‐6 family of cytokine initially considered as haematopoietic and cytoprotective factor. Recent evidence indicates that IL‐11 promotes lung fibrosis and pulmonary hypertension in animal models and is elevated in lung tissue of patients with pulmonary fibrosis and pulmonary hypertension. Fibrocytes are bone marrow‐derived circulating cells that participate in lung fibrosis and pulmonary hypertension, but the role of IL‐11 on fibrocytes is unknown. We investigated the role of IL‐11 system on fibrocyte activation in different in vitro and in vivo models of lung fibrosis associated with pulmonary hypertension. Experimental Approach Human fibrocytes were isolated from peripheral blood of six healthy donors. Recombinant human (rh)‐IL‐11 and soluble rh‐IL‐11 receptor, α subunit (IL‐11Rα) were used to stimulated fibrocytes in vitro to measure:‐ cell migration in a chemotactic migration chamber, fibrocyte to endothelial cell adhesion in a microscope‐flow chamber and fibrocyte to myofibroblast transition. Mouse lung fibrosis and pulmonary hypertension was induced using either IL‐11 (s.c.) or bleomycin (intra‐tracheal), while in the rat monocrotaline (intra‐tracheal) was used. In vivo siRNA‐IL‐11 was administered to suppress IL‐11 in vivo . Key Results RhIL‐11 and soluble rhIL‐11Rα promote fibrocyte migration, endothelial cell adhesion and myofibroblast transition. Subcutaneous (s.c.) IL‐11 infusion elevates blood, bronchoalveolar and lung tissue fibrocytes. SiRNA‐IL‐11 transfection in bleomycin and monocrotaline animal models reduces blood and lung tissue fibrocytes and reduces serum CXCL12 and CXCL12/CXCR4 lung expression. Conclusion and Implications Targeting IL‐11 reduces fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension‐associated lung fibrosis.