Extracellular glucose triggers metabolic reprogramming of cultured human bronchial epithelial cells and indirect fibroblast activation

Abstract

Glucose is essential for energy metabolism, and its usage can determine other cellular functions, depending on the cell type. In some pathological conditions, cells are exposed to high concentrations of glucose for extended periods. In this study, we investigated metabolic, oxidative stress, and cellular senescence pathways in human bronchial epithelial cells (HBECs) cultured in media with physiologically low (5 mm) and high (12.5 mm) glucose concentrations. HBECs exposed to 12.5 mm glucose showed increased glucose routing toward the pentose phosphate pathway, lactate synthesis, and glycogen, but not triglyceride synthesis. These metabolic shifts were not associated with changes in cell proliferation rates, oxidative stress, or cellular senescence pathways. Since hyperglycemia is associated with fibrosis in the lung, we asked whether HBECS could activate fibroblasts. Primary human lung fibroblasts cultured in media conditioned by 12.5 mm glucose‐exposed HBECs showed a 1.3‐fold increase in the gene expression of COL1A1 and COL1A2, along with twofold increased protein levels of smooth muscle cell actin and 2.4‐fold of COL1A1. Consistently, HBECs cultured with 12.5 mm glucose secreted proteins associated with inflammation and fibrosis, such as interleukins IL‐1β, IL‐10, and IL‐13, CC chemokine ligands CCL2 and CCL24, and with extracellular matrix remodeling, such as metalloproteinases (MMP)‐1, MMP‐3, MMP‐9, and MMP‐13 and tissue inhibitors of MMPs (TIMP)‐1 and ‐2. This study shows that HBECs undergo metabolic reprogramming and increase the secretion of profibrotic mediators following exposure to high concentrations of glucose, and it contributes to the understanding of the metabolic crosstalk of neighboring cells in diabetes‐associated pulmonary fibrosis.

Keywords

• epithelial cells
• fibroblast activation
• glucose
• metabolic reprogramming