Airway Epithelial Cell Responses to Ozone Injury

Abstract

The airway epithelial cells is an important target in ozone injury. Once activated, the airway epithelium responds in three phases. The initial, or immediate phase, involves activation of constitutive cells, often through direct covalent interactions including the formation of secondary ozonolysis products--hydroxyhydroperoxides, aldehydes, and hydrogen peroxide. Recently, we found hydroxyhydroperoxides to be potent agonists of bioactive eicosanoid formation by human airway epithelial cells in culture. Other probable immediate events include activation and inactivation of enzymes present on the epithelial surface (e.g., neutral endopeptidase). During the next 2 to 24 hr, or early phase, epithelial cells respond by synthesis and release of chemotactic factors, including chemokines--macrophage inflammatory protein-2, RANTES, and interleukin-8. Infiltrating leukocytes during this period also release elastase, an important agonist of epithelial cell mucus secretion and additional chemokine formation. The third (late) phase of ozone injury is characterized by eosinophil or monocyte infiltration. Cytokine expression leads to alteration of structural protein synthesis, with increases in fibronectin evident by in situ hybridization. Synthesis of epithelial antiproteases, e.g., secretory leukocyte protease inhibitor, may also increase locally 24 to 48 hr after elastase concentrations become excessive. Thus, the epithelium is not merely a passive barrier to ozone injury but has a dynamic role in directing the migration, activating, and then counteracting inflammatory cells. Through these complex interactions, epithelial cells can be viewed as the initiators (alpha) and the receptors (omega) of ozone-induced airway disease.

Upper airway inflammation in children exposed to ambient ozone and potential signs of adaptation

“…Also, ECP concentration and leukocyte count were elevated in autumn, when the ozone concentration had decreased. The present findings showing diminution of inflammatory markers in the NL of children under continuous O 3 exposure must therefore be interpreted with caution, since progressive epithelial damage was observed, even in the presence of functional adaptation [36]. Furthermore, it is not clear in how far nasal epithelium is representative of O 3 ‐induced changes in the lower airways.…”

“…Several authors have described mechanisms of adaptation following chronic exposure based on functional, biochemical and morphological studies in rats [32–35]. A dose‐dependent (0 ppm, 0.12 ppm and 1 ppm ozone) increase in activities of antioxidant enzymes, such as glutathione transferase and peroxidase as well as superoxide dismutase, was evoked through ozone exposure for 90 days and 20 months [34], which may reflect an active reaction of airway epithelial cells [36]. Thus, inactivation of free radicals by antioxidant substances could play a key role in the development of adaptation to O 3 and could, secondarily, interrupt the inflammatory effects of O 3 .…”

T cell depletion protects against alveolar destruction due to chronic cigarette smoke exposure in mice

“…We found slight changes in chemokine release by NECs after O 3 exposure ( Table 1). The factors measured here as well as others that can be produced by ECs, such as IL-4, IL-12, IL-15, or IL-18 or RANTES (17,44,58,64), can activate NK cells and also induce changes in NK cell immunophenotypes (73). Therefore, we tested whether soluble factors released by NECs can change NK cell activity.…”

Genes of Innate Immunity and the Biological Response to Inhaled Ozone

“…Airway epithelia are damaged after ozone inhalation, resulting in loss of cilliary function , increased epithelial permeability , and defects in mucocilliary clearance . In addition to barrier function, epithelia can also function as a central regulator of pulmonary immune responses . After exposure to ozone, epithelia release cytokines and growth factors, such as interleukin 6 (IL‐6), interleukin 8 (IL‐8), and tumor necrosis factor (TNF)‐α that can result in recruitment of neutrophils and monocytes .…”