Emerging Therapies in Pulmonary Fibrosis: A Common Pathway for the Action of Diverse Pharmacologic Agents

Fibrotic lung diseases are a heterogeneous set of disorders characterized by progressive infiltration of the pulmonary interstitium by inflammatory cells and fibroblasts, leading to destruction of normal pulmonary tissue and increased extracellular matrix deposition. Fibrotic lung disease can be initiated by numerous triggers—genetic, immunologic, pharmacologic, environmental, infectious—that share many downstream effectors, leading to injury patterns with substantial pathologic and clinical overlap. Recent preclinical studies have expanded our knowledge of the mechanisms of lung inflammation and implicated the key role of specific cytokines in the pathogenesis of lung inflammation. They reinforce the concept that inflammation is a key precursor of lung fibrosis. They have also identified specific intracellular signaling pathways that are modulated, at least in part, by cytokine signaling and that have been shown to be emerging targets for drugs that target inflammation in the lung. Recent advances in therapeutics have yielded two new drugs active in pulmonary fibrosis, the PDE4-selective inhibitor nerandomilast and the prostacyclin analog treprostinil. There is now compelling evidence that, despite their structural differences, these two drugs act through a common mechanism, the cAMP signaling pathway. The new clinical trial results have provided critical confirmation that these targets are indeed key regulators of lung fibrosis and inflammation and, in turn, have provided well-validated clinical evidence that these agents have therapeutic value in patients.