Abstract
BackgroundIndividuals with respiratory disease are being increasingly exposed to wildfire smoke as populations encroach further into forested regions and climate change continues to bring higher temperatures with lower rainfall. Frequent exposures have significant potential to accelerate conditions such as chronic obstructive pulmonary disease (COPD) which is characterised by an exaggerated inflammatory response to environmental stimuli. Here we employ models of human airway epithelium exposed to wildfire smoke-extract (WFSE) to examine modulation in airway epithelial cell (AEC) survival, fragility and barrier function.MethodsSubmerged cultures of small airway epithelial cells (SAEC) and differentiated air-liquid interface (ALI) cultures of primary bronchial AEC (bAEC) were treated for 1–24 h with 1–10% WFSE generated from plant species found in the Australian bushland. Autophagy (LC3-II and Sequestosome), apoptosis (Poly-(ADP)-Ribose Polymerase (PARP) cleavage) and tight junction proteins were measured using western blot. Barrier function was assessed via permeability of fluorescein tracers and measuring trans-epithelial electrical resistance. The production of IL-6 was assessed using ELISA.ResultsPrimary epithelial models exposed to WFSE exhibited a significant blockade in autophagy as evidenced by an increase in LC3-II coupled with a concomitant elevation in Sequestosome abundance. These exposures also induced significant PARP cleavage indicative of apoptotic changes. ALI cultures of bAEC treated with 5% WFSE demonstrated barrier dysfunction with significant increases in paracellular molecular permeability and ionic conductance, and a reduction in the abundance of the tight junction proteins ZO-1 and Claudin-1. These cultures also exhibited increased IL-6 secretion consistent with the aberrant and pro-inflammatory repair response observed in the COPD airways. Further, blocks in autophagy and barrier disruption were significantly elevated in response to WFSE in comparison to similar exposures with cigarette smoke-extract.ConclusionWFSE inhibits autophagic flux and induces barrier dysfunction in the airway epithelium. As autophagy is a central regulator of cellular repair, viability, and inflammation, targeting the block in autophagic flux may ameliorate the consequences of wildfire smoke-exposure for individuals with pre-existing respiratory conditions.
Highlights
The airway inflammation and remodelling observed during chronic obstructive pulmonary disease (COPD) is driven by exogenous noxious stimuli that activate the airway epithelium, which responds by releasing alarmins and pro-inflammatory factors that promote the recruitment of inflammatory cells [1, 2]
We report that while airway epithelial cell (AEC) exposed to wildfire smoke extract (WFSE) exhibited a similar tendency for unscheduled apoptosis when compared with cells exposed to cigarette smoke extract (CSE), wildfire smoke-extract (WFSE) produced a significant increase in epithelial permeability and blockade in autophagic flux
Wildfire smoke has a significant negative impact on the survival of AEC and the maintenance of the immunological barrier imparted by the airway epithelium
Summary
The airway inflammation and remodelling observed during chronic obstructive pulmonary disease (COPD) is driven by exogenous noxious stimuli that activate the airway epithelium, which responds by releasing alarmins and pro-inflammatory factors that promote the recruitment of inflammatory cells [1, 2]. In situations where people are exposed to intense heat or have a severe respiratory infection, co-exposure to prolonged periods of smoke may cause damage to the airway epithelium that promotes the pathogenesis of COPD [9]. This scenario is relevant in countries such as Australia, which has a high prevalence of respiratory disease and where agricultural communities are required to conserve highly combustible adjacent bushlands that have evolved with bushfires as a normal phenomenon that promotes revegetation [8]. We employ models of human airway epithelium exposed to wildfire smoke-extract (WFSE) to examine modulation in airway epithelial cell (AEC) survival, fragility and barrier function
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