Radiation-induced lung fibrosis is a common consequence of therapeutic thoracic irradiation, with 5-15% of patients developing significant loss of function, deterioration in the quality of life, and even death. Research into the pathogenesis of radiation-induced lung disease is urgently needed since there are no currently approved therapies. The cytokine TGF? plays a key role in promoting differentiation of fibroblasts to myofibroblasts and accumulation of resulting scar tissue. We recently published the exciting and novel finding that lung tissues of patients with lung fibrosis had highly elevated levels of lactic acid. We proposed that lactate in the extracellular matrix lowers the local pH, resulting in activation of latent TGF? that promotes fibrosis. We also discovered that the enzyme that produces lactate, lactate dehydrogenase (LDH), is itself upregulated by TGF?, creating a feed-forward loop that could promote and maintain lung fibrosis. Crucially, LDH is also regulated by the transcription factor HIF1?, which is activated following irradiation in lung cells. Thus, radiation could initiate this feed-forward loop via HIF1? mediated upregulation of lactate production, after which the lactate-TGF?-LDH cycle is self-perpetuating. The interplay of TGF?, LDH and HIF1? represents a novel regulatory axis and potential therapeutic target in radiation-induced fibrosis. Our overall hypothesis is that irradiation promotes lung fibrosis by upregulating HIF1? and lactate dehydrogenase, leading to activation of a pro-fibrotic feed-forward loop in which lactate activates latent TGF?, promoting fibrogenesis and further upregulation of lactate production. To test this hypothesis we have designed the following Specific Aims:
Specific Aim 1. Investigate the effect of ionizing radiation on lactate metabolism and production that contributes to lung scarring, and evaluate the efficacy of LDH inhibitors as potential therapeutic agents.
Specific Aim 2. Determine the effects of radiation exposure on LDH expression in vivo using human samples and a preclinical animal model, determine the mechanisms that regulate irradiation induced LDH expression, and investigate pharmacologic inhibition of LDH activity as a mitigation strategy. These studies will, for the first time, provide the key mechanistic data linking radiation with fibrosis via excess lactic acid production. We will evaluate exhaled lactate as a potential biomarker for disease progression and treatment efficacy, and we will provide critical proof-of concept data using human samples and preclinical animal models for inhibition of LDH as a novel and viable therapeutic target in radiation-induced lung fibrosis and other scarring diseases.

Public Health Relevance

Patients who receive radiation therapy for breast and lung cancers are at risk for development of lung fibrosis, a scarring disease that results in loss of function, permanent disability, and sometimes death. We have recently uncovered evidence that lung fibrosis patients produce elevated levels of lactic acid in their lungs, which we hypothesize causes lung scarring. In this project we will study the role of lactic acid in radiation-induced lug scarring to determine how it causes fibrosis, why it is dysregulated following radiation therapy, and whether inhibiting lactic acid production can be used as a new therapeutic strategy in radiation-induced lung fibrosis and other scarring diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127001-04
Application #
9610674
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Vuga, Louis J
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Lacy, Shannon H; Woeller, Collynn F; Thatcher, Thomas H et al. (2018) Activated Human Lung Fibroblasts Produce Extracellular Vesicles with Anti-Fibrotic Prostaglandins. Am J Respir Cell Mol Biol :
Lacy, Shannon H; Epa, Amali P; Pollock, Stephen J et al. (2018) Activated human T lymphocytes inhibit TGF?-induced fibroblast to myofibroblast differentiation via prostaglandins D2 and E2. Am J Physiol Lung Cell Mol Physiol 314:L569-L582
Judge, Jennifer L; Nagel, David J; Owens, Kristina M et al. (2018) Prevention and treatment of bleomycin-induced pulmonary fibrosis with the lactate dehydrogenase inhibitor gossypol. PLoS One 13:e0197936
Hansen, Trevor C; Woeller, Collynn F; Lacy, Shannon H et al. (2017) Thy1 (CD90) Expression Is Elevated in Radiation-Induced Periprosthetic Capsular Contracture: Implication for Novel Therapeutics. Plast Reconstr Surg 140:316-326
Judge, Jennifer L; Lacy, Shannon H; Ku, Wei-Yao et al. (2017) The Lactate Dehydrogenase Inhibitor Gossypol Inhibits Radiation-Induced Pulmonary Fibrosis. Radiat Res 188:35-43
Judge, J L; Owens, K M; Pollock, S J et al. (2015) Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase. Am J Physiol Lung Cell Mol Physiol 309:L879-87
Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L et al. (2015) Pharmacologic inhibition of lactate production prevents myofibroblast differentiation. Am J Physiol Lung Cell Mol Physiol 309:L1305-12