Determinants of initiation and progression of idiopathic pulmonary fibrosis

Abstract

IPF is a devastating disease with few therapeutic options. The precise aetiology of IPF remains elusive. However, our understanding of the pathologic processes involved in the initiation and progression of this disease is improving. Data on the mechanisms underlying IPF have been generated from epidemiologic investigations as well as cellular and molecular studies of human tissues. Although no perfect animal model of human IPF exists, pre-clinical animal studies have helped define pathways which are likely important in human disease. Epithelial injury, fibroblast activation and repetitive cycles of injury and abnormal repair are almost certainly key events. Factors which have been associated with initiation and/or progression of IPF include viral infections, abnormal cytokine, chemokine and growth factor production, oxidant stress, autoimmunity, inhalational of toxicants and gastro-oesophageal reflux disease. Furthermore, recent evidence identifies a role for a variety of genetic and epigenetic abnormalities ranging from mutations in surfactant protein C to abnormalities in telomere length and telomerase activity. The challenge remains to identify additional inciting agents and key dysregulated pathways that lead to disease progression so that we can develop targeted therapies to treat or prevent this serious disease.

Figure 1

Factors involved in the initiation and progression of IPF. A variety of repetitive insults leads to epithelial injury and cell recruitment and differentiation through activation of a variety of growth factors, cytokines and other mediators. Ultimately fibroblasts and myofibroblasts accumulate leading to deposition of excess extracellular matrix. CCL2, CC Chemokine Ligand 2; IGF-1, insulin-like growth factor; MCP-1, Monocyte chemoattractant protein-1; TGF-β, transforming growth factor-β; Th2, T helper cell type 2; TNF-α, Tumour Necrosis Factor-α.