Abstract
Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4μM [~300 μg/L (ppb)] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE) cell model we found that both micromolar (3.9 μM) and submicromolar (0.8 μM) arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl) Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-). We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway.
Highlights
It is well established that chronic exposure to arseniccontaminated drinking water can lead to obstructive lung disease (e.g., chronic obstructive pulmonary disease (COPD), bronchiectasis), reduced lung function, and other respiratory effects [1,2,3,4,5,6,7]
In this report we show that primary mouse tracheal epithelial (MTE) cells exposed to environmentally relevant levels of arsenic displayed reduced transepithelial resistance in culture, indicative of lost epithelial barrier integrity
In this report we have shown that conducting airway epithelial cells exposed to environmentally relevant levels of arsenic sustain altered barrier function and structure
Summary
It is well established that chronic exposure to arseniccontaminated drinking water can lead to obstructive lung disease (e.g., chronic obstructive pulmonary disease (COPD), bronchiectasis), reduced lung function, and other respiratory effects (e.g., chronic cough, chest sounds) [1,2,3,4,5,6,7]. Despite the laboratory evidence and strong links between arsenic and respiratory infection and subsequent illness, the arsenicinduced alterations in airway physiology that underlie these adverse lung effects remain largely unknown. The airway epithelial tight junction acts as a physical barrier to inhaled insults as well as a paracellular regulator of ion conductance (reviewed in 14,15). Breaches in this barrier can lead to pathogenic infiltration, chronic infection, and inflammation. A variety of transmembrane proteins that include a subset of claudins (Cl-1, Cl-3, Cl-4, Cl-5, and Cl-7), occludin, and JAM-A are expressed in conducting airway epithelial cells [21,22]
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