Abstract
Nanoparticle (NP) exposure has been closely associated with the exacerbation and pathophysiology of many respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. Mucus hypersecretion and accumulation in the airway are major clinical manifestations commonly found in these diseases. Among a broad spectrum of NPs, titanium dioxide (TiO2), one of the PM10 components, is widely utilized in the nanoindustry for manufacturing and processing of various commercial products. Although TiO2 NPs have been shown to induce cellular nanotoxicity and emphysema-like symptoms, whether TiO2 NPs can directly induce mucus secretion from airway cells is currently unknown. Herein, we showed that TiO2 NPs (<75 nm) can directly stimulate mucin secretion from human bronchial ChaGo-K1 epithelial cells via a Ca2+ signaling mediated pathway. The amount of mucin secreted was quantified with enzyme-linked lectin assay (ELLA). The corresponding changes in cytosolic Ca2+ concentration were monitored with Rhod-2, a fluorescent Ca2+ dye. We found that TiO2 NP-evoked mucin secretion was a function of increasing intracellular Ca2+ concentration resulting from an extracellular Ca2+ influx via membrane Ca2+ channels and cytosolic ER Ca2+ release. The calcium-induced calcium release (CICR) mechanism played a major role in further amplifying the intracellular Ca2+ signal and in sustaining a cytosolic Ca2+ increase. This study provides a potential mechanistic link between airborne NPs and the pathoetiology of pulmonary diseases involving mucus hypersecretion.
Highlights
Many published reports have demonstrated the association between NP exposure and pulmonary morbidity and mortality [1,2,3]
We investigated the role of the calcium-induced calcium release (CICR) mechanism by blocking Ryanodine receptors (RYRs) [20]
Our results revealed that CICR was largely inhibited by ryanodine resulting in a significantly diminished [Ca2+]C increase induced by NPs (Fig. 3B)
Summary
Many published reports have demonstrated the association between NP exposure and pulmonary morbidity and mortality [1,2,3]. During NP exposure, individuals with respiratory diseases showed more incidences of bronchoconstriction, medication use, bronchial hyperreactivity and lung fibrosis [2,7]. It has been reported that .50% of TiO2 NP exposed workers had respiratory symptoms accompanied by reduction in pulmonary function [10,11]. Other reports have indicated that inhalation of TiO2 NPs can induce pulmonary inflammatory responses (characterized by neutrophil recruitment), epithelial cell death and increased permeability [2,9]. TiO2 NPs have been shown to play a role in inducing epithelial fibroproliferative changes, stimulating goblet cell hyperplasia and in instigating emphysema-like (such as alveolar enlargement) damages in the lungs [2,10,12]. Nanotoxicity induced by TiO2 NP exposure in both the occupational and ambient environment presents a significant and realistic health concern
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