Ozone-dependent increases in lung glucocorticoids and macrophage response: Effect modification by innate stress axis function

Abstract

Although considerable inter-individual variability exists in health effects associated with air pollutant exposure, underlying reasons remain unclear. We examined whether innate differences in stress axis function modify lung glucocorticoid and macrophage responses to ozone (O₃). Highly-stress responsive Fischer (F344) and less responsive Lewis (LEW) rats were exposed for 4 h by nose-only inhalation to air or O₃ (0.8 ppm). Ozone increased corticosterone recovered by bronchoalveolar lavage in both strains (F344 > LEW). Higher corticosterone in F344 was associated with a blunted response to O₃ of macrophage pro-inflammatory genes compared to LEW. Pharmacological inhibition of O₃-dependent corticosterone production in F344 enhanced the inflammatory gene response to O_3, mimicking the LEW phenotype. Examination of potential impacts of glucocorticoids on macrophage function using a human monocyte-derived macrophage cell line (THP-1) showed that cortisol modified phagocytosis in a macrophage phenotype-dependent manner. Overall, our data implicate endogenous glucocorticoids in the regulation of pulmonary macrophage responses to O₃.

Keywords: Alveolar macrophage; Glucocorticoid; Inflammation; Ozone; Phagocytosis; Polarization.