Fibrosis in systemic sclerosis/scleroderma (SSc) is characterized by the progressive accumulation and persistence in multiple organs of pathologic fibroblasts whose contractile properties and exuberant secretion of collagens promote tissue stiffness and scarring. Identifying a tractable mechanism for inactivating and possibly clearing these ultimate effector cells of fibrosis, conventionally termed myofibroblasts (MFs), represents an appealing therapeutic strategy for patients with SSc. This can be accomplished by their phenotypic dedifferentiation, a process known to be promoted by generation of the intracellular second messenger cyclic AMP (cAMP). Notably, however, the abilities of SSc fibroblasts derived from different tissues to generate cAMP - and dedifferentiate in response to it - have never been directly characterized or compared. Here we compared these two processes in lung and skin MFs derived from patients with SSc. While directly increasing intracellular cAMP induced comparable dedifferentiation of lung and skin SSc MFs, dedifferentiation in response to the well-recognized cAMP stimulus prostaglandin E