Fibrosis, defined as the pathologic accumulation of extracellular matrix, is the final outcome of several common chronic inflammatory, immunemediated, and metabolic diseases and accounts for up to 45% of all deaths in the industrialized world. 1 The approval of pirfenidone and nintedanib for the treatment of idiopathic pulmonary fibrosis (IPF), a rapidly progressive and fatal fibrotic condition, represented a defining moment for the development of antifibrotic therapeutic agents. 2, 3 However, although these agents slow the decline in lung function, they do not halt disease progression, so IPF continues to represent a disease of high unmet clinical need. In this issue of the Journal, Richeldi and colleagues4 report on the promising results of a well-conducted phase 2, double-blind, placebocontrolled trial of BI 1015550, an oral preferential inhibitor of phosphodiesterase (PDE) 4B that has combined antifibrotic and antiinflammatory effects. The authors found that this agent, assessed as monotherapy or in combination with background antifibrotic therapy, prevented lungfunction decline in patients with IPF. The antifibrotic potential and long-term side-effect profile of this agent await verification in a phase 3 trial, but the finding that it is possible to evaluate the potential of new agents on the basis of a change from baseline in the forced vital capacity (FVC) within a relatively short, 12-week treatment window, even on a background of existing antifibrotic therapy, is a major step forward. It is also worth highlighting that the results of this trial support the usefulness of adopting a Bayesian statistical approach in which historical data are used to allow more patients to be randomly assigned to receive active treatment. The findings also raise intriguing questions regarding the mechanism by which BI 1015550 is acting, with implications for the future development of antifibrotic strategies. The currently favored paradigm for the pathogenesis of IPF proposes that this condition arises as a result of chronic epithelial microinjury and a resultant highly dysregulated wound-healing response, which is characterized by aberrant bidirectional epithelial–mesenchymal cross-talk in genetically predisposed older persons. The accumulation and persistence of hypersynthetic mesenchymalcell populations that are derived from multiple cellular sources, including the local proliferation and differentiation of resident lung fibroblasts under the influence of potent fibroblast mitogens and differentiation factors, are key events in the emergence of fibrotic foci (the hallmark lesions of IPF) and the progression of the fibrotic remodeling process.

Inflammation is also a feature of IPF, but the contribution of inflammation to disease progression remains controversial. The negative results of multicenter trials of antiinflammatory drugs led to a view that inflammation might represent an epiphenomenon. However, newer insights, which have been facilitated in part by the application of state-of-the-art genomic approaches, have led to a reevaluation of this view, particularly with respect to the loss of T-cell and B-cell tolerance and the emergence of profibrotic macrophage populations, which are likely to collaborate with stromal cells to promote a profibrogenic microenvironment in patients with IPF. 5 PDE4B is a member of the type IV, cyclic AMP (cAMP)–specific, cyclic nucleotide PDE family that plays a key role in signal transduction by regulating the cellular concentrations of cyclic nucleotides. The antiinflammatory and immunomodulatory effects of oral selective PDE4 inhibitors, which are mediated by the ability of these inhibitors to increase cAMP levels, underpin the approval of such agents for the treatment of certain …