MCT4 mediates hypoxia-induced extracellular lactate release from IPF fibroblasts

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Biochemistry

Background:

• Lactate is elevated in idiopathic pulmonary fibrosis (IPF) lungs and linked to fibrosis pathogenesis.
• IPF fibroblasts under hypoxia produce excess lactate via altered lactate dehydrogenase activity.
• The role of monocarboxylate transporter 4 (MCT4), a lactate exporter, in lung fibrosis is unstudied.

Purpose of the Study:

• To investigate the role of MCT4 in IPF fibroblast lactate production and lung fibrogenesis.
• To determine if MCT4 is upregulated in IPF fibroblasts and contributes to extracellular lactate accumulation.
• To explore the therapeutic potential of targeting MCT4 or lactate signaling in IPF.

Main Methods:

• Assessed MCT4 and MCT1 expression in control and IPF fibroblasts under hypoxia.
• Utilized pharmacologic inhibition and silencing of MCT4 to evaluate its effect on lactate export.
• Examined MCT4 expression in mouse models of lung injury and IPF patient lung tissue.
• Investigated the impact of IPF fibroblast-conditioned media on normal fibroblast differentiation and the role of MCT4 and GPR-81.

Main Results:

• MCT4 was significantly upregulated in IPF fibroblasts under hypoxic conditions, while MCT1 levels remained unchanged.
• Inhibition or silencing of MCT4 reduced extracellular lactate generation by IPF fibroblasts.
• MCT4 expression was elevated in bleomycin-injured mouse lungs and IPF patient lungs.
• Conditioned media from hypoxic IPF fibroblasts induced α-smooth muscle actin expression in normal fibroblasts, an effect attenuated by MCT4 or GPR-81 inhibition.

Conclusions:

• MCT4 plays a critical role in facilitating extracellular lactate production by IPF fibroblasts in hypoxic environments.
• Increased lactate export via MCT4 contributes to lung fibrogenesis and fibroblast differentiation.
• Targeting MCT4 or the lactate receptor GPR-81 presents a novel therapeutic strategy for IPF.