Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive and irreversible scarring disease of unknown origin. There are currently few effective treatments for IPF and the mechanisms of its pathogenesis are poorly understood. Our lab has shown that altered metabolic pathways may play a significant role in the pathogenesis of IPF. We have found that lung tissue from patients with IPF contains excess levels of the metabolite lactate, as well as increased expression of lactate dehydrogenase isozyme A (LDHA), the enzyme that converts pyruvate to lactate, in both lung epithelium and interstitium. Our previous studies have focused on the interstitial compartment and have elucidated the mechanisms by which lactate and LDHA overexpression in primary human lung fibroblasts leads to myofibroblast differentiation, the key scar forming cells in pulmonary fibrosis. Thus, our previous studies identified lactate as a novel and potent pro-fibrotic mediator. However, the current hypothesis in the field suggests that repetitive injury to the lung alveolar epithelium, aberrant epithelial-fibroblast communication, and lack of normal epithelial repair processes leads to myofibroblast differentiation, ultimately causing fibrosis. Therefore, for my research project, I will investigate the role of LDHA overexpression and lactate production in the lung alveolar epithelium in the context of epithelial-fibroblast crosstalk. I hypothesize that LDHA is up-regulated in alveolar epithelial cells in patients with IPF, and that LDHA overexpression in the lung epithelium in vivo is sufficient to initiate fibrosis. In this proposal I will determine i LDHA is up-regulated primary alveolar epithelial cells isolated from patients with IPF (Aim1), determine if LDHA overexpression in alveolar epithelial cells in vitro causes myofibroblast differentiation i fibroblasts in co-culture (Aim2), and determine if epithelial LDHA overexpression cause pulmonary fibrosis in vivo (Aim3). This project will help determine if the alveolar epithelium is a major contributor to the excess lactate found in IPF lungs, and will elucidate the mechanisms of epithelial-fibroblast crosstalk in the context of LDHA overexpression. Ultimately these studies will help determine if LDHA is a potential therapeutic target in the treatment of IPF.

Public Health Relevance

This research will fill gaps in our knowledge of the pathogenic mechanisms in pulmonary fibrosis, a scarring disease with very poor prognosis and few effective treatments. This project seeks to determine if altered metabolic pathways, namely lactate metabolism, in the lung epithelium play a key role in the development of pulmonary fibrosis. Knowledge gained from these have the potential to lead to new therapeutic interventions for pulmonary fibrosis and other organ fibroses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31HL132453-01
Application #
9123152
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Colombini-Hatch, Sandra
Project Start
2016-06-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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