Mechanistic basis for the antifibrotic actions of cAMP-based therapies

The human and economic impact of idiopathic pulmonary fibrosis and other interstitial lung diseases is enormous, and available therapies are of limited utility. A decade after the introduction of the first antifibrotic agents, two new agents are on the horizon. Nerandomilast is an inhibitor of phosphodiesterase 4B, while treprostinil is an analogue of prostacyclin. Both agents increase intracellular cAMP. Although the smooth muscle relaxant properties of agents that increase cAMP have long been leveraged for the treatment of airway and vascular diseases, potential antifibrotic actions of cAMP elevation are much less well appreciated by clinicians and researchers. The purpose of this review is to discuss the mechanistic underpinnings for a beneficial role of cAMP in fibrotic lung diseases. We briefly review the pathogenesis of fibrotic lung disease, the anatomy of the cAMP pathway, and the myriad ways in which this pathway is disrupted in fibrotic diseases. We then focus on the pleiotropic actions by which cAMP opposes the aberrant phenotypes of immune cells, fibroblasts, and epithelial cells that characterise fibrotic diseases. Finally, we highlight some unanswered questions about, and future opportunities for optimising, therapeutic interventions that leverage the cAMP pathway.