Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study

Abstract

IntroductionIdiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause characterised by progressive fibrotic formation in lung tissue. We hypothesise that disrupted metabolic pathways in IPF contribute to disease pathogenesis.MethodsMetabolomics of human IPF was performed using mass spectroscopy (IPF lung=8; donor lung=8). Gene expression of key metabolic enzymes was measured using microarrays. Of the 108 metabolites whose levels were found altered, 48 were significantly increased, whereas 60 were significantly decreased in IPF samples compared with normal controls.ResultsSpecific metabolic pathways mediating the IPF remodelling were found with a downregulated sphingolipid metabolic pathway but an upregulated arginine pathway in IPF. In addition, disrupted glycolysis, mitochondrial beta-oxidation and tricarboxylic acid cycle, altered bile acid, haem and glutamate/aspartate metabolism were found in IPF samples compared with control.ConclusionsOur results show alterations in metabolic pathways for energy consumption during lung structural remodelling, which may contribute to IPF pathogenesis. We believe that this is the first report of simultaneously and systemically measuring changes of metabolites involving nine metabolic pathways in human severe IPF lungs. The measurement of the metabolites may serve in the future diagnosis and prognosis of IPF.

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

“…Interestingly, metformin-treated cells also displayed upregulation of genes involved in sphingolipid metabolism (although less significantly) and downregulation of genes involved in arginine and proline metabolism. This corresponds to previous findings in human IPF lungs, reported to be characterized by reduced sphingolipid metabolism and increased arginine and proline metabolism 14 . The latter pathway is important for collagen synthesis.…”

“…In fact, metformin is known to disrupt mitochondrial complex I, thus inhibiting cellular respiration. Recently, Zhao et al published an extensive analysis of metabolic alterations in IPF lungs compared to donors 14 . They concluded that several types of long-and medium-chain fatty acids are enriched in IPF lungs 14 .…”

Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

“…Antidiabetic drugs might, therefore, be expected to have a beneficial effect on outcomes in IPF via an effect on glucose metabolism; however, we could not confirm this in the current analysis with metformin. Metformin reduces blood glucose levels mainly by inhibiting hepatic gluconeogenesis and increasing insulin sensitivity [40] and, therefore, may not target the pathways implicated in IPF pathogenesis by Zhao et al [21]. Thus, further research is required to determine whether other antidiabetic drugs with different glucose metabolic targets could be beneficial for patients with IPF and diabetes.…”

“…Interestingly, a recent metabolomic study has found that glycolysis and gluconeogenesis are altered in the lungs of patients with IPF [21], providing a possible mechanism by which diabetes could promote the development of IPF. Antidiabetic drugs might, therefore, be expected to have a beneficial effect on outcomes in IPF via an effect on glucose metabolism; however, we could not confirm this in the current analysis with metformin.…”

“…However, it should be noted that steroids, which were commonly used as a treatment for IPF before the introduction of antifibrotic agents, could have contributed to the development of diabetes in patients with IPF and may account, in part, for a potential link between IPF and diabetes [20]. Interestingly, recent metabolomic data have linked alterations in glucose metabolic pathways to structural remodeling of the lungs in patients with IPF [21], providing a potential mechanism by which diabetes could contribute to the pathogenesis of IPF.…”