Advances in our understanding of distal progenitors in idiopathic pulmonary fibrosis: implications for novel therapeutics.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease for which the only definitive treatment is lung transplantation. Currently available pharmacological treatments target the most obvious component of the disease, the accumulating mesenchymal tissue, and delay but do not prevent its relentlessly progressive course. However, it is now understood that IPF is a consequence of aberrant fibrotic repair in response to epithelial injury or to increased epithelial susceptibility to injury. The diversity of genetic and environmental risk factors underlying IPF raises the question whether mechanisms of epithelial dysfunction shared across all aetiologies for IPF exist. Deeper understanding of such mechanisms could lead to causative, disease-modifying treatments, but first requires insight into the identity of the epithelial drivers of IPF. Two schools of thought exist, which are not mutually exclusive. One focuses on type 2 alveolar epithelial (AT2) cells, the surfactant-producing cells in the alveoli that can also function as alveolar stem cells. The second school of thought sees a contribution of the distal airways to IPF pathogenesis. This article summarises the arguments in favour of each proposition, discusses the limitations of mouse models, which have supported a role for AT2 cells, and argues, based on studies in human lungs and organoid models, that the epithelium of the most distal airway branches, which are absent in rodents, may play a major role in IPF pathogenesis.