Document Detail


Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-β.
MedLine Citation:
PMID:  22923663     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Robert Matthew Kottmann; Ajit A Kulkarni; Katie A Smolnycki; Elizabeth Lyda; Thinesh Dahanayake; Rami Salibi; Sylvie Honnons; Carolyn Jones; Nancy G Isern; Jian Z Hu; Steven D Nathan; Geraldine Grant; Richard P Phipps; Patricia J Sime
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-23
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  186     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2012-12-26     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  740-51     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
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MeSH Terms
Descriptor/Qualifier:
Case-Control Studies
Cell Differentiation*
Gene Expression Regulation, Enzymologic
Humans
Hydrogen-Ion Concentration
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Idiopathic Pulmonary Fibrosis / metabolism*,  physiopathology
Isoenzymes / metabolism
L-Lactate Dehydrogenase / metabolism
Lactic Acid / metabolism*
Magnetic Resonance Spectroscopy
Myofibroblasts / metabolism*
Transforming Growth Factor beta / metabolism*
Up-Regulation
Grant Support
ID/Acronym/Agency:
1R21RR025785-01/RR/NCRR NIH HHS; HL 088325/HL/NHLBI NIH HHS; HL-075432/HL/NHLBI NIH HHS; HL-66988/HL/NHLBI NIH HHS; KL2 RR024136/RR/NCRR NIH HHS; KL2RR024136/RR/NCRR NIH HHS; P30ES01247/ES/NIEHS NIH HHS; T32 HL066988/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Isoenzymes; 0/Transforming Growth Factor beta; 50-21-5/Lactic Acid; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 1.1.1.27.-/lactate dehydrogenase 5
Comments/Corrections
Comment In:
Am J Respir Crit Care Med. 2013 Jul 1;188(1):111   [PMID:  23815725 ]
Am J Respir Crit Care Med. 2013 Jul 1;188(1):111-2   [PMID:  23815724 ]
Am J Respir Crit Care Med. 2012 Oct 15;186(8):701-3   [PMID:  23071184 ]

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