Idiopathic pulmonary fibrosis (IPF) is a chronic human disease with persistent destruction
of lung parenchyma. A pivotal role in the initiation and pathogenesis of IPF is played
by transforming growth factor (TGF)-β1 signaling. As shown herein, TGF-β1 signaling
down-regulates not only peroxisome biogenesis but also the metabolism of these organelles
in human IPF fibroblasts. In accordance with the in vitro cell culture observations in human fibroblasts and human lung tissue, peroxisomal
biogenesis and metabolic proteins were significantly down-regulated in the lung of
1-month–old transgenic mice expressing a constitutively active TGF-β type I receptor
(ALK5). In the opposite direction, the peroxisome biogenesis protein PEX13p as well
as the peroxisomal lipid metabolic enzyme ACOX1 and antioxidative enzyme catalase
were enormously up-regulated in TGF-β type II receptor and Smad3 knockout mice. A
novel mechanism of peroxisome biogenesis and metabolic regulation via TGF-β1–Smad
signaling is reported in this study: by demonstrating the interaction of the Smad3
transcription factor with the PEX13 gene in chromatin immunoprecipitation–on–chip assay as well as in a bleomycin-induced
pulmonary fibrosis model applied to TGF-β type II receptor knockout mice. Taken together,
TGF-β1 participates in regulation of peroxisomal biogenesis and metabolism via Smad-dependent
signaling, opening novel strategies for the development of therapeutic approaches
that might inhibit pulmonary fibrosis progression in patients with IPF.
Graphical abstract
Graphical Abstract
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The American Journal of PathologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-beta signaling.Proc Natl Acad Sci U S A. 2015; 112: E2048-E2057
- Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis.Proc Natl Acad Sci U S A. 1991; 88: 6642-6646
- Liver fibrosis.J Clin Invest. 2005; 115: 209-218
- Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10.Eur Respir J. 2003; 22: 69-76
- Reciprocal regulation of TGF-beta and reactive oxygen species: a perverse cycle for fibrosis.Redox Biol. 2015; 6: 565-577
- A novel profibrotic mechanism mediated by TGFbeta-stimulated collagen prolyl hydroxylase expression in fibrotic lung mesenchymal cells.J Pathol. 2015; 236: 384-394
- Amplification of TGFbeta induced ITGB6 gene transcription may promote pulmonary fibrosis.PLoS One. 2016; 11: e0158047
- Acute exacerbations of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2007; 176: 636-643
- A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092
- Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082
- Nintedanib treatment for idiopathic pulmonary fibrosis patients who have been switched from pirfenidone therapy: a retrospective case series study.J Clin Med. 2020; 9: 422
- Specificity and versatility in TGF-beta signaling through Smads.Annu Rev Cell Dev Biol. 2005; 21: 659-693
- Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell. 2003; 113: 685-700
- Asbestos-derived reactive oxygen species activate TGF-beta1.Lab Invest. 2004; 84: 1013-1023
- The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo.J Immunotoxicol. 2008; 5: 145-149
- Epithelium-specific deletion of TGF-beta receptor type II protects mice from bleomycin-induced pulmonary fibrosis.J Clin Invest. 2011; 121: 277-287
- Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L585-L593
- Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma.Arthritis Rheum. 2007; 56: 334-344
- Peroxisomes in mouse and human lung: their involvement in pulmonary lipid metabolism.Histochem Cell Biol. 2008; 130: 719-740
- Peroxisomes in airway epithelia and future prospects of these organelles for pulmonary cell biology.Histochem Cell Biol. 2009; 131: 447-454
- Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism.J Lipid Res. 2010; 51: 2863-2895
- Peroxisomal metabolism and oxidative stress.Biochimie. 2014; 98: 56-62
- Peroxisome metabolism and cellular aging.Traffic. 2011; 12: 252-259
- Peroxisomes are oxidative organelles.Antioxid Redox Signal. 2010; 13: 525-537
- Redox interplay between mitochondria and peroxisomes.Front Cell Dev Biol. 2015; 3: 35
- Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease?.Thorax. 2000; 55: 189-193
- Deletion of a single allele of the Pex11beta gene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain.Dis Model Mech. 2012; 5: 125-140
- Peroxisome biogenesis disorders.Biochim Biophys Acta. 2006; 1763: 1733-1748
- Conditional inactivation of the TGF-beta type II receptor using Cre:Lox.Genesis. 2002; 32: 73-75
- Manipulation of transgenes by site-specific recombination: use of Cre recombinase.Methods Enzymol. 1993; 225: 890-900
- Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer.BMC Biol. 2013; 11: 111
- Generation of mice with conditionally activated transforming growth factor beta signaling through the TbetaRI/ALK5 receptor.Genesis. 2008; 46: 724-731
- Peroxisomes in human and mouse testis: differential expression of peroxisomal proteins in germ cells and distinct somatic cell types of the testis.Biol Reprod. 2007; 77: 1060-1072
- Limma powers differential expression analyses for RNA-sequencing and microarray studies.Nucleic Acids Res. 2015; 43: e47
- Visualizing genomic data using Gviz and Bioconductor.Methods Mol Biol. 2016; 1418: 335-351
- Peroxisomes in cardiomyocytes and the peroxisome/peroxisome proliferator-activated receptor-loop.Thromb Haemost. 2015; 113: 452-463
- A new immunomodulatory role for peroxisomes in macrophages activated by the TLR4 ligand lipopolysaccharide.J Immunol. 2017; 198: 2414-2425
- Idiopathic pulmonary fibrosis.Lancet. 2011; 378: 1949-1961
- Pirfenidone in idiopathic pulmonary fibrosis.Eur Respir J. 2010; 35: 821-829
- Transforming growth factor beta differentially regulates expression of integrin subunits in guinea pig airway epithelial cells.J Biol Chem. 1992; 267: 17409-17414
- Intraperoxisomal redox balance in mammalian cells: oxidative stress and interorganellar cross-talk.Mol Biol Cell. 2011; 22: 1440-1451
- Peroxisomes, lipid metabolism, and peroxisomal disorders.Mol Genet Metab. 2004; 83: 16-27
- Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury.J Biol Chem. 2004; 279: 32804-32812
- Hereditary catalase deficiencies and increased risk of diabetes.Lancet. 2000; 356: 1820-1821
- Peroxisome-mediated metabolism is required for immune response to microbial infection.Immunity. 2017; 47: 93-106.e7
- SMAD proteins directly suppress PAX2 transcription downstream of transforming growth factor-beta 1 (TGF-beta1) signalling in renal cell carcinoma.Oncotarget. 2018; 9: 26852-26867
- Smad proteins suppress CCAAT/enhancer-binding protein (C/EBP) beta- and STAT3-mediated transcriptional activation of the haptoglobin promoter.J Biol Chem. 2001; 276: 24719-24725
- A functional SMAD2/3 binding site in the PEX11beta promoter identifies a role for TGFbeta in peroxisome proliferation in humans.Front Cell Dev Biol. 2020; 8: 577637
- The role of PPARs in lung fibrosis.PPAR Res. 2007; 2007: 71323
- Stimulation of peroxisome-proliferator-activated receptor alpha (PPAR alpha) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts.Clin Sci (Lond). 2002; 103: 284S-288S
- The peroxisome proliferator-activated receptor alpha activator fenofibrate inhibits endothelin-1-induced cardiac fibroblast proliferation.J Cardiovasc Pharmacol. 2004; 44: S279-S282
- Role of endogenous and exogenous ligands for the peroxisome proliferator-activated receptor alpha in the development of bleomycin-induced lung injury.Shock. 2005; 24: 547-555
- Adrenoleukodystrophy, cerebrohepatorenal syndrome (Zellweger syndrome), and peroxisomes.Pediatr Pathol. 1985; 3: 377-378
- Histopathologic approach to metabolic liver disease: part 1.Pediatr Dev Pathol. 1998; 1: 179-199
Article info
Publication history
Published online: December 12, 2022
Accepted:
November 4,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Supported by JLU Giessen-Institute for Anatomy and Medical Cell Biology, Children's Hospital Los Angeles, Saban Research Institute–NIH HL141352, DZL–German Center for Lung Research–Deutsches Zentrum für Lungenforschung.
G.O. and S.K. contributed equally to this work.
Disclosures: None declared.
Current address of G.O., Department of Internal Medicine, Medical Clinic II, UKGM Giessen, Giessen, Germany; of S.K., Institute for Anatomy and Cell Biology, Julius Maximilians University, Würzburg, Germany.
Identification
Copyright
© 2022 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.
