期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 61, 期 8, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00154-17
关键词
airway inflammation; Pseudomonas aeruginosa; cystic fibrosis; host defense peptides; theta defensin
资金
- Cystic Fibrosis Foundation [BERING14GO]
- Cystic Fibrosis Research Inc.
- Webb Foundation
- National Institute of Dental and Craniofacial Research [5T90DE021982]
- National Institute of General Medicine [F31GM109729]
- National Institutes of Health [RO1AI22931, R01DE021341, RO1AI125141]
- Arthritis Foundation
- National Cancer Institute [P30CA014089]
- USC Immune Monitoring Core Facility
- National Cancer Institute Cancer Center Shared Grant [P30CA014089]
Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease. We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models. We evaluated RTD-1's effects on basal and Pseudomonas aeruginosa-induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety, and tolerance studies were performed in naive mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burdens and airway inflammation using an established model of chronic P. aeruginosa endobronchial infection in CF (Delta F508) mice. RTD-1 directly reduces metalloprotease activity, as well as inflammatory cytokine secretion from CF airway leukocyte and bronchial epithelial cells. Intrapulmonary safety, tolerability, and stability data support the aerosol administration route. RTD-1 reduced the bacterial lung burden, airway neutrophils, and inflammatory cytokines in CF mice with chronic P. aeruginosa lung infection. Collectively, these studies support further development of RTD-1 for treatment of CF airway disease.
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