Abstract
Asthma is a chronic lung disease that causes airflow obstruction due to airway inflammation. However, its therapeutics remain inadequate. We previously reported that phospholipase D1 (PLD1) is a key enzyme involved in the production of pro-inflammatory cytokines in airway inflammation induced by the house dust mite allergen Dermatophagoides farinae 2 (Der f 2). We also revealed that PLD1 is specifically inactivated by AP180 (assembly protein, 180 kDa) and identified the PLD1-specific binding motif (TVTSP) of AP180. Therefore, the aims of this study were to develop a novel anti-asthmatic agent that could suppress airway inflammation by inhibiting PLD1 and examine its acute and chronic toxicity. We designed TAT-TVTSP, a PLD1-inhibitory peptide fused with a cell-penetrating peptide (CPP) delivery system. TAT-TVTSP was efficiently delivered to bronchial epithelial cells and significantly reduced Der f 2-induced PLD activation and Interleukin 13 (IL-13) production. Intranasally administered TAT-TVTSP was also efficiently transferred to airway tissues and ameliorated airway inflammation in a Der f 2-induced allergic asthma mouse model. Moreover, we investigated the safety of TAT-TVTSP as a therapeutic agent through single- and repeated-dose toxicity studies in a mouse model. Taken together, these results indicated that a PLD1-inhibitory peptide fused with a cell-penetrating peptide may be useful for treating allergic inflammatory asthma induced by house dust mites (HDMs).
Highlights
Allergic asthma is a heterogeneous inflammatory lung disease that affects ~334 million people worldwide[1,2]
TAT-TVTSP was found to be relatively safe in single- and repeated-dose toxicity studies of a mouse model. These findings indicate that therapy using a PLD1inhibitory peptide fused with a cell-penetrating peptide (CPP) delivery system can be an efficient and promising strategy to prevent allergic asthma induced by house dust mites (HDMs)
We investigated whether a peptide in the phospholipase D1 (PLD1)-specific binding motif of AP180 was applicable as an inhibitor of airway inflammation induced by the house dust mite allergen Der f 2
Summary
Allergic asthma is a heterogeneous inflammatory lung disease that affects ~334 million people worldwide[1,2]. Patients with asthma are prescribed inhaled corticosteroids with or without longlasting ß agonists, theophyllines, or leukotriene-receptor antagonists, according to their symptoms[3]. These anti-asthmatic therapies are limited to symptomatic treatment and may incur severe side effects. Despite receiving multiple therapies, ~40% of patients with asthma remain symptomatic, and up to 5% have difficultto-control asthma[3,4]. In this context, many researchers have focused on improving disease control by studying methods to reduce the administration of corticosteroids
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