title: Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-β.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.affiliation: Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Robert Matthew
authors.initials: RM
authors.lastname: Kottmann
authors.forename: Ajit A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Katie A
authors.initials: KA
authors.lastname: Smolnycki
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lyda
authors.forename: Thinesh
authors.initials: T
authors.lastname: Dahanayake
authors.forename: Rami
authors.initials: R
authors.lastname: Salibi
authors.forename: Sylvie
authors.initials: S
authors.lastname: Honnons
authors.forename: Carolyn
authors.initials: C
authors.lastname: Jones
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Isern
authors.forename: Jian Z
authors.initials: JZ
authors.lastname: Hu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Nathan
authors.forename: Geraldine
authors.initials: G
authors.lastname: Grant
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D016022:Case-Control Studies; D002454:Cell Differentiation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D058628:Myofibroblasts / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D016212:Transforming Growth Factor beta; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5