Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that preferentially affects older people. This progressive disease is characterised by irreversible stiffening of lung tissue that culminates in impaired function and respiratory failure. The average survival from diagnosis is 3.5-4.5 years, with current treatments aimed at slowing disease progression. Drugs that can reverse the fibrosis and repair damaged lungs are desperately needed. In order to achieve this, we need to understand the mechanisms of disease, specifically in older patients.
In this issue, Daniel Veyel and colleagues have completed the most comprehensive metabolomic and lipidomic analysis in a mouse model of IPF to date. The researchers induced pulmonary fibrosis by treating mice with bleomycin. Mass spectrometry analyses of the fibrotic tissue showed extensive alterations in the metabolomic and lipidomic profiles. These changes were indicative of tissue remodelling and repair, with increased collagen synthesis and extracellular matrix turnover being prominent features. Upregulated energy-producing pathways were also present in the IPF model, which could reflect increased energy demand of the fibrotic tissue. Furthermore, IPF model mice displayed upregulation of phospholipids, sphingolipids and eicosanoids, suggesting increased inflammatory signalling.
Importantly, this study compared young and old mice. Although metabolomic and lipidomic profiles were similar, older mice were more susceptible to fibrosis at lower doses of the IPF-inducing agent. Furthermore, despite the trends of metabolomic and lipidomic alterations being similar in the two age groups, fold changes of some metabolic pathways differed.
Overall, this study mapped fibrotic changes, tissue remodelling, energy metabolism and inflammation in the metabolome and lipidome of lungs from an IPF mouse model. The subtle differences in susceptibility and response to fibrosis induction between young and old mice suggest that age should be considered when designing pre-clinical and clinical trials for IPF. Crucially, many of the alterations in the IPF mouse model recapitulated studies of human IPF, and the novel findings prompt further investigation of potential therapeutic targets for IPF.
Figure shows micro-computed tomography images of mouse lungs illustrating the degree of fibrosis in the lung fibrosis mouse model (Bleo) compared to controls (Ctrl). Credit: Stephan Klee and Janine Beier.
