Nerandomilast mechanism of action: preferential phosphodiesterase 4B inhibition in the treatment of pulmonary fibrosis

Interstitial lung disease (ILD) is an umbrella term for a large group of diseases of the lung tissue that can lead to pulmonary fibrosis, with the potential to become progressively fibrotic. The most common progressive fibrosing ILD is idiopathic pulmonary fibrosis. However, patients with other ILDs may develop a progressive disease behavior, termed progressive pulmonary fibrosis. Progressive fibrosing lung disease develops when chronic overexpression of pro-fibrotic and pro-inflammatory mediators drive a self-sustaining process of fibrosis and inflammation through multiple signaling pathways via fibroblasts, epithelial cells, and immune cells, leading to excessive extracellular matrix deposition and impairment of pulmonary function. Cyclic adenosine monophosphate (cAMP) is a key intracellular signaling molecule that plays a role in regulating inflammatory and fibrotic pathways. Phosphodiesterase 4 (PDE4) enzymes regulate cAMP levels via hydrolysis. The PDE4B subtype is highly expressed in lung tissue and the immune system and is therefore an attractive target for treating pulmonary fibrosis. In this animated video article, we show the pathophysiology of pulmonary fibrosis and demonstrate the molecular and cellular mechanisms of action of nerandomilast, a novel pharmacotherapy. Nerandomilast is a preferential inhibitor of PDE4B with antifibrotic, immunomodulatory, and vascular effects, which intervene in the pathogenesis of pulmonary fibrosis.