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      Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study

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          Abstract

          Introduction

          Idiopathic 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.

          Methods

          Metabolomics 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.

          Results

          Specific 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.

          Conclusions

          Our 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.

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          Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy.

          Tim Oury, Cheryl Fattman, Kathrine R. Tan … (2005)
          Idiopathic ulmonary fibrosis (histopathology of usual interstitial pneumonia) is a progressive lung disease of unknown etiology. No treatment has been shown to improve the prognosis of the patients with this disease. Recent evidence, including the observations that the patients with idiopathic pulmonary fibrosis have higher levels of oxidant stress than control patients, and a recent multicenter European study examining the effect of the antioxidant N-acetylcysteine on the progression of idiopathic pulmonary fibrosis suggest that the cellular redox state may play a significant role in the progression of this disease. These complex mechanisms include activation of growth factors as well as regulation of matrix metalloproteinases and protease inhibitors. Potential future approaches for the therapy of interstitial pulmonary fibrosis may involve synthetic agents able to modulate cellular redox state. Investigation into therapeutic approaches to inhibit oxidant-mediated reactions in the initiation and progression of pulmonary fibrosis may provide hope for the future treatment of this disease.
          Article 0 comments Cited 107 times – based on 0 reviews     Review now
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            Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure.

            Steven H. Abman, Thanh Le, N. Markham … (2002)
            To determine whether disruption of vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling in the newborn has long-term effects on lung structure and function, we injected 1-day-old newborn rat pups with a single dose of Su-5416, a VEGFR inhibitor, or vehicle (controls). Lungs from infant (3-wk-old) and adult (3- to 4-mo-old) rats treated with Su-5416 as newborns showed reductions in arterial density (82 and 31%, respectively) and alveolar counts (45 and 29%) compared with controls. Neonatal treatment with Su-5416 increased right ventricle weight to body wt ratios (4.2-fold and 2.0-fold) and pulmonary arterial wall thickness measurements (2.7-fold and 1.6-fold) in infant and adult rats, respectively, indicating marked pulmonary hypertension. We conclude that treatment of newborn rats with the VEGFR inhibitor Su-5416 impaired pulmonary vascular growth and postnatal alveolarization and caused pulmonary hypertension and that these effects were long term, persisting well into adulthood.
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              Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition.

              Javier Milara, Esteban Morcillo, Gustavo Scillato-Yané … (2012)
              Idiopathic pulmonary fibrosis (IPF) is characterised by the aberrant epithelial to mesenchymal transition (EMT) and myofibroblast accumulation. Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1) have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown. S1P levels were measured in serum (n=27) and bronchoalveolar lavage (BAL; n=15) from patients with IPF and controls (n=30 for serum and n=15 for BAL studies). SPHK1 expression was measured in lung tissue from patients with IPF (n=12) and controls (n=15). Alveolar type II transformation into mesenchymal cells was studied in response to S1P (10(-9)-10(-5) M). The median (IQR) of S1P serum levels was increased in patients with IPF (1.4 (0.4) μM) versus controls (1 (0.26) μM; p<0.0001). BAL S1P levels were increased in patients with IPF (1.12 (0.53) μM) versus controls (0.2 (0.5); p<0.0001) and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity (Spearman's r=-0.87, -0.72 and -0.68, respectively) in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with α-smooth muscle actin, vimentin and collagen type I (Spearman's r=0.82, 0.85 and 0.72, respectively). S1P induced EMT in alveolar type II cells by interacting with S1P(2) and S1P(3), as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-β1 (TGF-β1) release. Furthermore, TGF-β1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-β1 and the S1P/SPHK1 axis. S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT.
              Article 0 comments Cited 60 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMJ Open Respir Res
                Journal ID (iso-abbrev): BMJ Open Respir Res
                Journal ID (hwp): bmjresp
                Journal ID (publisher-id): bmjopenrespres
                Title: BMJ Open Respiratory Research
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2052-4439
                Publication date Collection: 2017
                Publication date (Electronic): 5 June 2017
                Volume: 4
                Issue: 1
                Electronic Location Identifier: e000183
                Affiliations
                [1 ] departmentDepartment of Thoracic Surgery , University Health Network , Toronto, Ontario, Canada
                [2 ] departmentDepartment of Medicine , Queen's University , Kingston, Ontario, Canada
                [3 ] departmentDivision of Respirology , University Health Network , Toronto, Ontario, Canada
                Author notes
                [Correspondence to ] Dr. Yidan D Zhao; yidanzhao@ 123456gmail.com and Dr. Marc de Perrot; Marc.DePerrot@ 123456uhn.ca

                YDZ and LY contributed equally.

                Article
                Publisher ID: bmjresp-2017-000183
                DOI: 10.1136/bmjresp-2017-000183
                PMC ID: 5531310
                PubMed ID: 28883924
                SO-VID: 48995b97-234f-46fe-aac4-0d86fe75da66
                Copyright © © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
                License:

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                Date received : 09 February 2017
                Date revision received : 15 March 2017
                Date accepted : 16 March 2017
                Funding
                Funded by: TGH Research Fundation;
                Categories
                Subject: Interstitial Lung Disease
                Subject: 1506
                Subject: 2220
                Custom metadata
                special-feature unlocked

                Keywords: interstitial fibrosis,lung transplantation
                Data availability:
                Keywords: interstitial fibrosis, lung transplantation

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