Ozone-induced eosinophil recruitment to airways is altered by antigen sensitization and tumor necrosis factor-αblockade

Abstract

Ozone is an atmospheric pollutant that causes lung inflammation and airway hyperresponsiveness. Ozone's effects occur in two distinct phases that are mediated by different populations of eosinophils. In the acute phase 1 day after exposure, mature airway‐resident eosinophils alter parasympathetic nerve function that results in airway hyperresponsiveness. At this time point, the severity of hyperresponsiveness correlates with the number of eosinophils in close proximity to airway nerves, but not with eosinophils in bronchoalveolar lavage. Three days later, newly divided eosinophils are recruited to airways by a tumor necrosis factor‐α‐dependent mechanism. These new eosinophils paradoxically attenuate ozone‐induced airway hyperresponsiveness. Ozone's effects on airway tissue eosinophils and nerve‐associated eosinophils 3 days after exposure are unknown. Thus, we tested ozone's effects on eosinophils in airway subepithelium and around airway nerves 1 and 3 days after ozone in nonsensitized and ovalbumin‐sensitized guinea pigs with or without the tumor necrosis factor‐α antagonist, etanercept, and compared changes in eosinophils with ozone‐induced airway hyperresponsiveness. More eosinophils were present in small, noncartilaginous airways and along small airway nerves compared to large cartilaginous airways in all treatment groups. The number of airway and nerve‐associated eosinophils were unaffected 1 day after ozone exposure, whereas significantly fewer airway eosinophils were present 3 days later. Airway and nerve‐associated eosinophils were also decreased in small airways 3 days after ozone in sensitized animals. These changes were blocked by etanercept. Airway eosinophils, but not nerve‐associated or bronchoalveolar lavage eosinophils correlated with airway hyperresponsiveness 3 days after ozone. Our findings indicate ozone causes persistent alterations in airway eosinophils and reinforce the importance of characterizing eosinophils’ effects within distinct airway compartments.

Transcriptional Effects of Ozone and Impact on Airway Inflammation

“…The effects of ozone on lung inflammation and AHR are biphasic and are mediated, at least in part, by distinct eosinophil populations (84). The acute 1-day effect of ozone is associated with the presence of mature airway-resident eosinophils in close proximity to parasympathetic nerves causing AHR.…”

The mode of action of anticholinergics in asthma

“…M 2 receptor dysfunction is thought to be driven by eosinophils and the secretion of major basic protein [10, 12]. In addition, tumour necrosis factor-α appears to play a key role in driving M 2 autoreceptor dysfunction in animal models of ozone- and virus-induced airway hyperreactivity [13, 14]. The increase in acetylcholine signalling on M 1 and M 3 receptors, and the M 2 receptor dysfunction, may all contribute to the increased bronchoconstriction, mucus secretion, inflammation and airway remodelling, as discussed in the following sections.…”

Eosinophil and airway nerve interactions in asthma

“…Consequently, newly divided bone marrow-derived eosinophils do not arrive in the airways and ozone-induced airway hyperreactivity persists in sensitized animals 3 days after exposure. 85 These findings have important implications for asthmatics exposed to environmental ozone. Ozone is a well-established precipitant of asthma exacerbations and approximately half of all asthmatics are sensitized to aero-allergens.…”

“…Eosinophils fail to expand in bone marrow after ozone in antigen‐sensitized animals. Consequently, newly divided bone marrow‐derived eosinophils do not arrive in the airways and ozone‐induced airway hyperreactivity persists in sensitized animals 3 days after exposure . These findings have important implications for asthmatics exposed to environmental ozone.…”