MCT4 mediates hypoxia-induced extracellular lactate release from IPF fibroblasts.

Lactate is increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in mice with experimental lung fibrosis, and lactate has been linked to the pathogenesis of lung fibrosis. IPF fibroblasts in hypoxic conditions generate increased lactate due to an imbalance of lactate dehydrogenase isoforms that induce pyruvate conversion to lactate. Monocarboxylate transporter 4 (MCT4) functions as a key lactate export protein, but its role has not been studied in lung fibrosis. We hypothesized that MCT4 would have a critical role in the ability of IPF fibroblasts to generate extracellular lactate and found that MCT4 was significantly upregulated in IPF fibroblasts under hypoxic conditions. In contrast, the lactate importer protein, monocarboxylate transporter 1 (MCT1) did not significantly change in control or IPF fibroblasts. Pharmacologic inhibition and silencing of MCT4 reduced extracellular lactate generation by IPF fibroblasts. Supporting its role in lung fibrogenesis, MCT4 was increased in bleomycin-injured mice and in lungs from IPF patients. Importantly, normal fibroblasts incubated with conditioned media from IPF fibroblasts exposed to hypoxic conditions had increased α-smooth muscle actin expression that was attenuated by inhibition of MCT4 in the donor IPF fibroblasts or by inhibition of the lactate receptor GPR-81 in the recipient normal fibroblasts. Together, these findings implicate MCT4 in the ability of IPF fibroblasts to increase extracellular lactate and highlight the role of lactate signaling via G-protein coupled receptor-81 in normal fibroblast differentiation. We propose a novel paradigm in which lactate export, driven by increased MCT4 expression, promotes fibrosis in oxygen-deficient microenvironments.