Abstract
Epithelial barrier dysfunction, characteristic of allergic airway disease may be, at least in part, due to the action of allergen-associated protease activities. Cockroach allergy is a major global health issue, with cockroaches containing considerable serine trypsin-like protease (TLP) activity. The present study sought to evaluate two novel protease inhibitors (PE-BBI and pLR-HL), recently isolated from amphibian skin secretions, for their potential to neutralise cockroach TLP activity and to determine any protective effect on cockroach-induced airway epithelial barrier disruption. Inhibitor potencies against the cockroach-associated activities were determined using a fluorogenic peptide substrate-based activity assay. 16HBE14o- cells (16HBE; a bronchial epithelial cell line) were treated with cockroach extract (CRE) in the presence or absence of the compounds in order to assess cell viability (RealTime Glo luminescent assay) and epithelial barrier disruption (transepithelial resistance and paracellular dextran flux). PE-BBI potently and selectively inhibited CRE TLP activity (pIC50 -8), but not host (16HBE) cell surface activity, which conferred protection of 16HBE cells from CRE-induced cell damage and barrier disruption. Novel protease inhibitor strategies such as PE-BBI may be useful for the treatment of allergic airway disease caused by cockroach proteases.
Highlights
Sensitization and exposure to allergens is a risk factor for allergic respiratory disease including asthma, which is a chronic condition affecting approximately 340 million people worldwide [1]
The airway epithelium forms a crucial barrier at the interface between the host and the inhaled environment protecting against microorganisms, airborne irritants and allergens [3]
Disruption of the airway epithelial barrier enables allergens to interact with subepithelial dendritic cells that results in naïve T cells becoming T-helper 2 (Th2) cells [3]
Summary
Sensitization and exposure to allergens is a risk factor for allergic respiratory disease including asthma, which is a chronic condition affecting approximately 340 million people worldwide [1]. Allergic sensitisation results from complex interactions between the allergen and the host with the airway epithelium representing the first site of interaction [2]. The airway epithelium forms a crucial barrier at the interface between the host and the inhaled environment protecting against microorganisms, airborne irritants and allergens [3]. Aeroallergens and other co-factors (e.g., cigarette smoke, pollution) interact with epithelial innate immune receptors including Toll-like and protease-activated receptors, which results in elevated production of pro-inflammatory cytokines that drive T-helper 2 (Th2)-like adaptive immunity [3]. Disruption of the airway epithelial barrier enables allergens to interact with subepithelial dendritic cells that results in naïve T cells becoming Th2 cells [3]
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