Lung Research Poster Session

David Ziehr, MD

Research Fellow
Pulmonary and Critical Care
David R. Ziehr, MD*, Kevin J. Leahy, MS, Jack Varon, MD, Rebecca M. Baron, MD, Edy Kim, MD PhD, Rachel S. Knipe, MD, William M. Oldham, MD PhD
Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) has high mortality and few therapies. IPF myofibroblasts rely on glycolysis and lactate production to sustain a pro-fibrotic disease phenotype. Monocarboxylate transporters MCT1 and MCT4 export lactate to facilitate continued glycolysis. We hypothesized that MCTs support glycolysis in IPF and MCT inhibition reduces lung fibrosis in experimental models.

Methods: Normal human lung fibroblasts (LFs) were treated with TGF-β to induce myofibroblast differentiation. We inhibited MCT1 and/or MCT4 with the small molecules AZD3965 and VB124, respectively. The effects of MCT inhibition on cellular bioenergetics were quantified using the Seahorse Extracellular Flux Analyzer. We measured cellular metabolites with LC-MS. We measured expression of αSMA by immunoblot as a marker of myofibroblast differentiation. Bleomycin was administered to C57BL/6N mice to induce pulmonary fibrosis. Treatment with daily VB124 began 7 days later and, at day 21, fibrosis severity was assessed by lung physiology and histology. MCT1, MCT4, and αSMA were analyzed by immunoblot and immunofluorescence from lung tissue from patients with IPF.

Results: Inhibition of MCT1 and MCT4 increased oxidative phosphorylation and decreased glycolysis in vitro. MCT1 or MCT4 inhibition decreased myofibroblast differentiation. In bleomycin-treated mice, VB124 produced less weight loss, improved lung compliance, and less histologic evidence of lung injury compared to vehicle-treated animals. Tissue from IPF patients demonstrated increased αSMA, MCT1, and MCT4 expression.

Conclusions: Inhibition of lactate export shifts fibroblast metabolism from glycolysis to oxidative phosphorylation, prevents myofibroblast differentiation, and alleviates lung fibrosis in vivo. Lactate transport is a promising therapeutic target in IPF.