the differential impact of pde4 subtypes in human lung fibroblasts on cytokineinduced proliferation and myofibroblast conversion lung fibroblast proliferation and differentiation into myofibroblasts are pathological key events during development of lung fibrosis cyclic nucleotide signaling is described as a negative modulator of these cellular processes and cyclic nucleotide degrading type 4 phosphodiesterases pde4 are important regulators of these pathways in this study we elucidated expression and the role of individual subtypes of pde4 in primary normal human lung fibroblast nhlf in controlling cytokinesinduced proliferation and conversion to myofibroblasts by shortinterfering rnas sirnas induced knockdown we verified the expression of pde4a b and d while pde4c was only minor or even not expressed in nhlf an efficient liposomemediated transfection method for mrna silencing and a knockdown of the expressed pde4 subtypes was achieved in these cells this knockdown was further validated by pde4 protein expression analysis and pde4 activity measurements functionally the knockdown of pde4a and pde4b inhibited proliferation induced by the cytokine combination of bfgf and il1 whereas knockdown of pde4d was ineffective in contrast tgf induced differentiation into myofibroblasts was affected by knockdown of pde4b and pde4d but not by pde4a knockdown in summary our data allow to assign different pde4 subtypes to distinct functions of human lung fibroblasts and highlight the predominant role of pde4b in controlling pathophysiological processes of human lung fibroblasts this provides a scientific rationale for focused therapeutic targeting of pde4b to treat respiratory diseases with fibrotic lesions in the lung