Abstract
Biomass fuel smoke is thought to contribute to chronic obstructive pulmonary disease, which is characterized by mucous cell metaplasia and enhanced mucus secretion. We investigated the effect of particulate matter (PM) with a diameter <2.5 μm (PM2.5) from wood smoke (WSPM2.5) on the expression of the most prominent secreted mucin, MUC5AC. Wood smoke was able to induce MUC5AC expression in the rat respiratory tract after 3 months of exposure. WSPM2.5 could induce MUC5AC production in both primary human airway epithelial cells and the NCI-H292 cell line. This induction process was mediated by activation of epithelial growth factor receptor (EGFR)-extracellular signal-regulated kinase (ERK) signaling through an EGFR ligand-dependent mechanism. Amphiregulin (AR) was identified as the major ligand responsible for EGFR-ERK signaling activation and MUC5AC expression. In turn, EGFR-ERK pathway activation was found to contribute to the de novo synthesis of AR. This positive feedback loop might play an important role in a sustained mucus hypersecretion response.
Highlights
Chronic obstructive pulmonary disease (COPD), a major increasing global public health problem, is estimated to become the world’s third leading cause of death by 20201
We show that WSPM2.5 up-regulates MUC5AC production, that the activation of Epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinase (ERK) signaling via the autocrine effects of the EGFR ligand AR and secreted AR further contribute to AR expression in a positive feedback loop, and that the EGFR-ERK pathway plays an indispensable role in this process
WSPM2.5 induces MUC5AC expression in primary epithelial cells cultured at the air-liquid interface
Summary
Chronic obstructive pulmonary disease (COPD), a major increasing global public health problem, is estimated to become the world’s third leading cause of death by 20201. Unlike other fossil fuel combustion chemicals, the health effects of PM from wood smoke remain poorly studied. We recently provided direct evidence that chronic exposure to biomass fuel induces pulmonary changes in rats consistent with those observed in COPD lungs, including airway mucus hypersecretion[21]. These observations led us to investigate, whether the cellular responses to WSPM2.5 involved MUC5AC secretion, focusing on the EGFR-ERK pathway. We show that WSPM2.5 up-regulates MUC5AC production, that the activation of EGFR-ERK signaling via the autocrine effects of the EGFR ligand AR and secreted AR further contribute to AR expression in a positive feedback loop, and that the EGFR-ERK pathway plays an indispensable role in this process
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