Ozone-induced enhancement of airway hyperreactivity in rhesus macaques: Effects of antioxidant treatment

• Published in: Journal of allergy and clinical immunology 2020-01, Vol.145 (1), p.312-323
• Main Authors: Flayer, Cameron H., Larson, Erik D., Joseph, Anjali, Kao, Sean, Qu, Wenxiu, Van Haren, Austin, Royer, Christopher M., Miller, Lisa A., Capitanio, John P., Sielecki, Thais, Christofidou-Solomidou, Melpo, Haczku, Angela
• Format: Article
• Language: English
• Subjects: air pollution; airway inflammation; Animals; Antioxidants - pharmacology; Asthma; Asthma - chemically induced; Asthma - drug therapy; Asthma - immunology; Butylene Glycols - pharmacology; CD4-Positive T-Lymphocytes - immunology; Dendritic Cells - immunology; Female; Glucosides - pharmacology; Macaca mulatta; Male; Myeloid Cells - immunology; nonhuman primate; Ozone - toxicity; therapies (investigational)
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2019.08.034

Ozone (O3) inhalation elicits airway inflammation and impairs treatment responsiveness in asthmatic patients. The underlying immune mechanisms have been difficult to study because of the lack of relevant experimental models. Rhesus macaques spontaneously have asthma and have a similar immune system to human subjects. We sought to investigate mucosal immune changes after O3 inhalation in a clinically relevant nonhuman primate asthma model and to study the effects of an antioxidant synthetic lignan (synthetic secoisolariciresinol diglucoside [LGM2605]). A cohort of macaques (n = 17) previously characterized with airway hyperreactivity (AHR) to methacholine was assessed (day 1). Macaques were treated (orally) with LGM2605 (25 mg/kg) or placebo twice per day for 7 days, exposed to 0.3 ppm O3 or air for 6 hours (on day 7), and studied 12 hours later (day 8). Lung function, blood and bronchoalveolar lavage (BAL) fluid immune cell profile, and bronchial brushing and blood cell mRNA expression were assessed. O3 induced significant BAL fluid neutrophilia and eosinophilia and increased AHR and expression of IL6 and IL25 mRNA in the airway epithelium together with increased BAL fluid group 2 innate lymphoid cell (ILC2s), CD1c+ myeloid dendritic cell, and CD4+ T-cell counts and diminished surfactant protein D expression. Although LGM2605 attenuated some of the immune and inflammatory changes, it completely abolished O3-induced AHR. ILC2s, CD1c+ myeloid dendritic cells, and CD4+ T cells are selectively involved in O3-induced asthma exacerbation. The inflammatory changes were partially prevented by antioxidant pretreatment with LGM2605, which had an unexpectedly disproportionate protective effect on AHR. [Display omitted]