Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-β
Open accessAbstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. Methods: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-β activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; α-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-β. TGF-β induced expression of LDH5 via hypoxia-inducible factor 1α (HIF1α). Importantly, overexpression of both HIF1α and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-β to induce differentiation. Furthermore, inhibition of both HIF1α and LDH5 inhibited TGF-β–induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-β. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.
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From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [64]
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- Authors
- Kottmann, R. M., Kulkarni, A. A., Smolnycki, K. A., Lyda, E., Dahanayake, T., Salibi, R., Honnons, S., Jones, C., Isern, N. G., Hu, J. Z., Nathan, S. D., Grant, G., Phipps, R. P., & Sime, P. J.
- Affiliations
- University of Rochester Medicine (US)
- Department of Medicine
- Department of Pathology
- Department of Thoracic Surgery
- Pacific Northwest National Laboratory (US)
- George Mason University (US)
- Corresponding author
- Sime, Patricia J.
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-10
- Volume
- 186
- Issue
- 8
- Pages
- 740-751
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- PMC
- PMC3480515
- OpenAlex
- W2009466546
- Cited by
- 415
- References
- 34
- Citations by year
- 2026: 55 · 2025: 49 · 2024: 46 · 2023: 57 · 2022: 32 · 2021: 43 · 2020: 30 · 2019: 17 · 2018: 19 · 2017: 22 · 2016: 13 · 2015: 14 · 2014: 8 · 2013: 9 · 2012: 1
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy
- National Institutes of Health (HL066988)
- National Heart, Lung, and Blood Institute (HL 66988, R01HL088325, T32HL066988, R01HL075432, HL075432, HL088325)
- National Institute of Environmental Health Sciences (P30 ES0 1247, P30ES001247)
- National Center for Research Resources (R21RR025785, KL2RR024136)
- Biological and Environmental Research
- Pacific Northwest National Laboratory
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- idiopathic pulmonary fibrosis, lactic acid, myofibroblast differentiation, TGF-beta, LDH5, hypoxia-inducible factor-1α, lung fibroblasts, lung metabolism
- MeSH terms
- Lactate Dehydrogenase 5, Cell Differentiation, Humans, Hydrogen-Ion Concentration, Isoenzymes, L-Lactate Dehydrogenase, Magnetic Resonance Spectroscopy, Up-Regulation, Gene Expression Regulation, Enzymologic, Case-Control Studies, Transforming Growth Factor beta, Lactic Acid, Hypoxia-Inducible Factor 1, alpha Subunit, Idiopathic Pulmonary Fibrosis, Myofibroblasts, In Vitro Techniques
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