AIRWAY EPITHELIAL-CELL RESPONSES TO OZONE INJURY

The airway epithelial cell is an important target in ozone injury. Onc e activated, the airway epithelium responds in three phases. The initi al, or immediate phase, involves activation of constitutive cells, oft en through direct covalent interactions including the formation of sec ondary ozonolysis products-hydroxyhydroperoxides, aldehydes, and hydro gen peroxide. Recently, we found hydroxyhydroperoxides to be potent ag onists of bioactive eicosanoid formation by human airway epithelial ce lls in culture. Other probable immediate events include activation and inactivation of enzymes present on the epithelial surface (e.g., neut ral endopeptidase). During the next 2 to 24 hr, or early phase, epithe lial cells respond by synthesis and release of chemotactic factors, in cluding chemokines-macrophage inflammatory protein-2, RANTES, and inte rleukin-8. Infiltrating leukocytes during this period also release ela stase, an important agonist of epithelial cell mucus secretion and add itional chemokine formation. The third (late) phase of ozone injury is characterized by eosinophil or monocyte infiltration. Cytokine expres sion leads to alteration of structural protein synthesis, with increas es in fibronectin evident by in situ hybridization. Synthesis of epith elial antiproteases, e.g., secretory leukocyte protease inhibitor, may also increase locally 24 to 48 hr after eiastase concentrations becom e excessive. Thus, the epithelium is not merely a passive barrier to o zone injury but has a dynamic role in directing the migration, activat ing, 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.