title: Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase.
abstract: Pulmonary fibrosis is a common and dose-limiting side-effect of ionizing radiation used to treat cancers of the thoracic region. Few effective therapies are available for this disease. Pulmonary fibrosis is characterized by an accumulation of myofibroblasts and excess deposition of extracellular matrix proteins. Although prior studies have reported that ionizing radiation induces fibroblast to myofibroblast differentiation and collagen production, the mechanism remains unclear. Transforming growth factor-β (TGF-β) is a key profibrotic cytokine that drives myofibroblast differentiation and extracellular matrix production. However, its activation and precise role in radiation-induced fibrosis are poorly understood. Recently, we reported that lactate activates latent TGF-β through a pH-dependent mechanism. Here, we wanted to test the hypothesis that ionizing radiation leads to excessive lactate production via expression of the enzyme lactate dehydrogenase-A (LDHA) to promote myofibroblast differentiation. We found that LDHA expression is increased in human and animal lung tissue exposed to ionizing radiation. We demonstrate that ionizing radiation induces LDHA, lactate production, and extracellular acidification in primary human lung fibroblasts in a dose-dependent manner. We also demonstrate that genetic and pharmacologic inhibition of LDHA protects against radiation-induced myofibroblast differentiation. Furthermore, LDHA inhibition protects from radiation-induced activation of TGF-β. We propose a profibrotic feed forward loop, in which radiation induces LDHA expression and lactate production, which can lead to further activation of TGF-β to drive the fibrotic process. These studies support the concept of LDHA as an important therapeutic target in radiation-induced pulmonary fibrosis.
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York; Lung Biology and Disease Program, University of Rochester, Rochester, New York.
authors.forename: J L
authors.initials: JL
authors.lastname: Judge
authors.affiliation: Department of Medicine, Pulmonary and Critical Care Medicine, University of Rochester, Rochester, New York; and.
authors.forename: K M
authors.initials: KM
authors.lastname: Owens
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York;
authors.forename: S J
authors.initials: SJ
authors.lastname: Pollock
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York;
authors.forename: C F
authors.initials: CF
authors.lastname: Woeller
authors.affiliation: Department of Medicine, Pulmonary and Critical Care Medicine, University of Rochester, Rochester, New York; and Lung Biology and Disease Program, University of Rochester, Rochester, New York.
authors.forename: T H
authors.identifier: http://orcid.org/0000-0001-7177-3041
authors.initials: TH
authors.lastname: Thatcher
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York;
authors.forename: J P
authors.initials: JP
authors.lastname: Williams
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York; Department of Medicine, Pulmonary and Critical Care Medicine, University of Rochester, Rochester, New York; and Lung Biology and Disease Program, University of Rochester, Rochester, New York.
authors.forename: R P
authors.initials: RP
authors.lastname: Phipps
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, New York; Department of Medicine, Pulmonary and Critical Care Medicine, University of Rochester, Rochester, New York; and Lung Biology and Disease Program, University of Rochester, Rochester, New York.
authors.forename: P J
authors.initials: PJ
authors.lastname: Sime
authors.affiliation: Department of Medicine, Pulmonary and Critical Care Medicine, University of Rochester, Rochester, New York; and Lung Biology and Disease Program, University of Rochester, Rochester, New York matt_kottmann@urmc.rochester.edu.
authors.forename: R M
authors.initials: RM
authors.lastname: Kottmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000528:radiation effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006072:Gossypol / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000096:biosynthesis; D008168:Lung / Q000201:enzymology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D058628:Myofibroblasts / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects*; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000209:etiology; D011832:Radiation Injuries / Q000201:enzymology / Q000209:etiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016212:Transforming Growth Factor beta; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D006072:Gossypol
keywords: ionizing radiation; lactate; lactate dehydrogenase; myofibroblast; pulmonary fibrosis