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Title: Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β

Abstract

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 tissuefrom patients with IPFanddeterminedthe effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-b activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; a-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-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a (HIF1a). Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b–induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acidmore » as an important mediator of myofibroblast differentiation via a pHdependent activation of TGF-b. 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.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1054443
Report Number(s):
PNNL-SA-89313
42296; 400412000
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
American Journal of Respiratory and Critical Care Medicine, 186(8):740-751
Additional Journal Information:
Journal Name: American Journal of Respiratory and Critical Care Medicine, 186(8):740-751
Country of Publication:
United States
Language:
English
Subject:
Environmental Molecular Sciences Laboratory

Citation Formats

Kottman, R M, Kulkarni, Ajit A, Smolnycki, Katie A, Lyda, Elizabeth, Dahanayake, Thinesh, Salibi, Rami, Honnons, Sylvie, Jones, Carolyn, Isern, Nancy G, Hu, Jian Z, Nathan, Steven D, Grant, Geraldine, Phipps, Richard P, and Sime, Patricia J. Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β. United States: N. p., 2012. Web. doi:10.1164/rccm.201201-0084OC.
Kottman, R M, Kulkarni, Ajit A, Smolnycki, Katie A, Lyda, Elizabeth, Dahanayake, Thinesh, Salibi, Rami, Honnons, Sylvie, Jones, Carolyn, Isern, Nancy G, Hu, Jian Z, Nathan, Steven D, Grant, Geraldine, Phipps, Richard P, & Sime, Patricia J. Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β. United States. https://doi.org/10.1164/rccm.201201-0084OC
Kottman, R M, Kulkarni, Ajit A, Smolnycki, Katie A, Lyda, Elizabeth, Dahanayake, Thinesh, Salibi, Rami, Honnons, Sylvie, Jones, Carolyn, Isern, Nancy G, Hu, Jian Z, Nathan, Steven D, Grant, Geraldine, Phipps, Richard P, and Sime, Patricia J. 2012. "Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β". United States. https://doi.org/10.1164/rccm.201201-0084OC.
@article{osti_1054443,
title = {Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor-β},
author = {Kottman, R M and Kulkarni, Ajit A and Smolnycki, Katie A and Lyda, Elizabeth and Dahanayake, Thinesh and Salibi, Rami and Honnons, Sylvie and Jones, Carolyn and Isern, Nancy G and Hu, Jian Z and Nathan, Steven D and Grant, Geraldine and Phipps, Richard P and Sime, Patricia J},
abstractNote = {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 tissuefrom patients with IPFanddeterminedthe effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-b activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; a-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-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a (HIF1a). Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b–induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pHdependent activation of TGF-b. 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.},
doi = {10.1164/rccm.201201-0084OC},
url = {https://www.osti.gov/biblio/1054443}, journal = {American Journal of Respiratory and Critical Care Medicine, 186(8):740-751},
number = ,
volume = ,
place = {United States},
year = {Mon Oct 15 00:00:00 EDT 2012},
month = {Mon Oct 15 00:00:00 EDT 2012}
}