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‘If you want to understand today you have to search yesterday’ wrote the American novelist Pearl Buck, and such is the challenge facing those who hope to disentangle the pathogenesis of idiopathic pulmonary fibrosis (IPF). The disease is characterised by the insidious but progressive development of fibrosis that culminates in respiratory failure and death, usually within 5 years of diagnosis. Despite recent advances in pathogenetic understanding, IPF remains a disease in need of effective treatments.
Following the reclassification of the idiopathic interstitial pneumonias 10 years ago,1 our understanding of the natural history of IPF has increased exponentially. Yet there remain lacunae in our knowledge of the disease: what does the earliest lesion of IPF look like and, even more importantly, what triggers its development and early progression? In most cases of IPF, extensive fibrosis is already established at the time of diagnosis. Much in the same way that cosmologists strive to infer the origins of the universe from modern-day movements of stars and planets, researchers hoping to understand the initiating events in pulmonary fibrosis have to do so by studying events that occur in established disease.
At a molecular level, IPF is characterised by the apparently unopposed activation of multiple profibrotic pathways involved in wound healing.2 The purpose of the normal wound healing process is to restore tissue integrity, structure and function following injury. In early wound healing, tissue expansion is associated with migration to the site of injury of fibroblasts that then proliferate, transform into myofibroblasts and rapidly synthesise extracellular matrix.3 In healthy individuals, the profibrotic phase of tissue repair then switches off and resorption of the extracellular matrix, with fibroblast apoptosis and architectural remodelling of tissue, occurs. In IPF, in contrast, several strands of evidence point strongly to a pivotal role for repetitive alveolar epithelial injury, resulting …