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

Abstract

Background: Ozone (O 3) 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. Objectives: We sought to investigate mucosal immune changes after O 3 inhalation in a clinically relevant nonhuman primate asthma model and to study the effects of an antioxidant synthetic lignan (synthetic secoisolariciresinol diglucoside [LGM2605]). Methods: A cohort of macaques (n 5 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 O 3 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. Results: O 3 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 1 myeloid dendritic cell, and CD4 1 T-cell counts and diminished surfactant protein D expression. Although LGM2605 attenuated some of the immune and inflammatory changes, it completely abolished O 3-induced AHR.

Sustained Effects on Lung Function in Community Members Following Exposure to Hazardous PM2.5 Levels from Wildfire Smoke

“…Past studies in air pollution have focused on the effects of pollutants on the airway epithelial lining and subsequent activation of the innate immune system. Recent studies have shown that ozone, a major toxic air pollutant, induces IL-33 production by airway epithelial cells that results in activation of type 2 innate lymphoid cells (ILC2) [30,31]. The ILC2 are important sources of IL-13 [32] and have been linked to asthma, an obstructive lung pathology.…”

Sustained Effects on Lung Function in Community Members Following Exposure to Hazardous PM2.5 Levels from Wildfire Smoke

“…Past studies in air pollution have focused on the effects of pollutants on the airway epithelial lining and subsequent activation of the innate immune system. Recent studies have shown that ozone, a major toxic air pollutant, induces IL-33 production by airway epithelial cells that results in activation of type 2 innate lymphoid cells (ILC2) (33,34). The ILC2 are important sources of IL-13 (35) and have been linked to asthma, an obstructive lung pathology.…”

Ozone-Induced Oxidative Stress, Neutrophilic Airway Inflammation, and Glucocorticoid Resistance in Asthma

“…In addition, O 3 -induced exacerbation of Th2-type airway inflammation in allergen challenged mice was associated with the appearance of abnormal, lower order oligomeric molecular formations of SP-D. Interestingly, in asthmatic rhesus macaques, O 3 induced de-oligomerization of SP-D was restored by treatment with a flaxseed derivative anti-oxidant (94). Thus, oxidative damage can cause conformational change in the SP-D molecule resulting in a potential loss of its immunoprotective function (91,213).…”

“…In healthy human subjects exposed to O 3 under experimental conditions, a significant airway neutrophilia was associated with a decrease in lung function (7,147,150) indicating the pathological significance of these cells. Interestingly, when O 3 exposure is combined with allergic sensitization in mouse models, asthmatic non-human primates (rhesus macaques) and in allergic human subjects, a marked influx of both eosinophilic and neutrophilic granulocytes is observed (10,94,101,106). While neutrophilia in healthy volunteers could be attenuated by fluticasone propionate ( 147), studies on mice (107), dogs (151) rhesus macaques (152), and asthma patients (153,154) showed controversial results on the effectiveness of glucocorticoids in inhibiting O 3 -induced exacerbation of asthmatic airway inflammation.…”

“…Amongst the environmental causes our review is focused on inhalational exposure to the toxic air pollutant, ozone (O 3 ) as it was found to be a significant contributor to respiratory illness. Specifically, O 3 induces airway hyperreactivity in mouse models of asthma (6,86,87,89,91,(98)(99)(100)(101)(102)(103)(104)(105)(106)(107), in Th2 low asthma in rhesus macaques (94,108) and in healthy human subjects and patients with asthma and COPD (6,7,59,(109)(110)(111)(112)(113)(114)(115)(116). Ground-level (tropospheric) O 3 is generated by the action of sunlight's UV rays from precursors (mostly air pollutants containing hydrocarbons, volatile organic compounds [VOC] and nitrogen oxides emitted during fossil fuel combustion).…”