Mapping the metabolomic and lipidomic changes in the bleomycin model of pulmonary fibrosis in young and aged mice

Abstract

Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the Bleomycin mouse model of IPF we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids, lipids and ECM turnover. Energy production was upregulated, including glycolysis, tricarboxylic acid (TCA) cycle, glutaminolysis, lactate production and increased fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Since the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the Bleomycin-induced pulmonary fibrosis model. Surprisingly, except cytidine, we did not detect any significantly differential metabolites or lipids between old and young Bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation that might serve for improving diagnostic and therapeutic options for fibrotic lung diseases in the future.

Time and phenotype-dependent transcriptome analysis in AAV-TGFβ1 and Bleomycin-induced lung fibrosis models

“…Therefore, aging is one important disease-contributing factor that requires studies with cellular resolution. Notably, there is a rapidly growing number of single-cell studies in the field of lung fibrosis 59 – 64 , and first examples for the integration of transcriptomic and proteomic data 55 , 65 as well as a rising number of metabolomics and lipidomics studies, including one that compared young and aged mice 66 , all of which steadily increase our understanding of the complex interplay and levels of regulation during PF pathogenesis. Still, given that all these studies made use of the Bleomycin model, we consider our AAV-TGFβ model and data a very valuable addition to the field.…”

Changes in serum metabolomics in idiopathic pulmonary fibrosis and effect of approved antifibrotic medication

“…Interestingly also in other types of organ fibrosis an increase in triglycerides was noted such as chronic kidney disease and fibrotic liver diseases (Chen et al, 2017;Monteillet et al, 2018;Harzandi et al, 2021). In addition, an increase in triglycerides was also observed in several murine models of organ fibrosis (Harzandi et al, 2021;Weckerle et al, 2021). In contrast, patients with cancer including lung malignancies show a down-regulation of triglycerides, which is associated with poor outcome (Siemianowicz et al, 2000).…”

Piglet cardiopulmonary bypass induces intestinal dysbiosis and barrier dysfunction associated with systemic inflammation

“…Metabolomic profiling for eicosanoids and short-chain fatty acids was performed when there was sufficient remaining stool sample. Eicosanoids were quantitated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) as previously described ( Salomon et al, 2021 ) and similarly to other metabolomic approaches ( Weckerle et al, 2022 ). Analysis of the eicosanoids and SCFAs involved converting the raw data to concentration data (ng/g for stool weight) using the Lab Solution software (version 5.99) (Shimadzu Scientific, Columbia, MD, USA).…”