Budesonide promotes airway epithelial barrier integrity following double-stranded RNA challenge

Abstract

Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption in vivo, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.

The Role of Defective Epithelial Barriers in Allergic Lung Disease and Asthma Development

“…Inhaled corticosteroids and β2-adrenoreceptor agonists are the firstline medications used in asthma treatment and are effective in most patients. Several data indicate that glucocorticoids (GCs) inhalation therapy, including budesonide, can improve epithelial barrier integrity and might contribute to the therapeutic effects of GCs for treating asthma 164,165 or chronic rhinosinusitis with nasal polyps. 166 Similarly, other GCs, including mometasone and fluticasone, were shown to be effective in restoring nasal epithelial barrier dysfunction in allergic rhinitis.…”

“…167 In animal models, budesonide was also proved to inhibit airway remodeling in the early stage of allergen-induced airway hyperresponsiveness (AHR), however it did not reverse established AHR. 168,169 Interestingly, neither formoterol nor Montelukast, were shown to promote barrier integrity, 165 suggesting that β2-adrenoreceptor agonists and anti-leukotrienes themselves might not have any positive effect on epithelial barrier restoration. In severe asthma patients, the long-term oral corticosteroid (CS) therapy is associated with serious side effects.…”

The airway epithelium: an orchestrator of inflammation, a key structural barrier and a therapeutic target in severe asthma

“…Montelukast has been shown to suppress cysteinyl leukotriene-induced disruption of tight and adherens junctions in human airway epithelial cells [56]. In vitro studies suggest that the corticosteroids dexamethasone and budesonide can restore epithelial cell junctions and barrier integrity [57][58][59]. However, corticosteroid treatment can elicit time-and concentrationdependent epithelial cell death, resulting in barrier dysfunction [60,61].…”

“…• Restores epithelial cell junctions and barrier integrity [57][58][59] • May inhibit MUC5AC/5B expression and goblet cell metaplasia [221] • Reduces RBM thickness by reducing deposition of ECM components [172,173] • Reduces airway inflammation [99][100][101][102] • Reduces the infiltration of immune cells into lung tissue [108,109] Montelukast (LTRA)…”

Airway Epithelial-Derived Immune Mediators in COVID-19

“…In addition, it can also suppress IL-6, IL-8, CCL5, and CXCL10 release from the BEAS-2B airway epithelial cell line in a dose-dependent manner following rhinovirus infection [ 169 ]. Budesonide can attenuate the barrier disruption caused by dsRNA treatment in in vivo murine and in vitro airway epithelial models [ 170 ]. It therefore may further reduce the infiltration of viral PAMPs and sensitization by sub-epithelial immune cells.…”