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Alterations in lung injury and gene expression following 2 weeks of episodic ozone exposure
Citation:
Moore, M., H. Nguyen, M. Schladweiler, R. Grindstaff, J. Richards, U. Kodavanti, J. Dye, AND C. Miller. Alterations in lung injury and gene expression following 2 weeks of episodic ozone exposure. Society of Toxicology, Nashville, TN, March 19 - 23, 2023.
Impact/Purpose:
The goal of this study was to understand the effects of episodic ozone on lung responses compared to an acute exposure. Abstract for Society of Toxicology conference March 2023
Description:
Ozone-induced acute lung injury and inflammation following one or two days of exposure are not evident if ozone exposure continues for 3 or more days. While a one-to-two-day exposure can induce neutrophilic inflammation, lung protein leakage, and airway irritation, real-life exposures to ozone are more likely to occur in an episodic fashion. Chronic exposure to ozone has been associated with cardiopulmonary disease. The goal of this study was to understand the effects of episodic ozone on lung responses compared to an acute exposure. Subsequently, an episodic exposure paradigm was established where, over the course of 2-weeks, rats were exposed to ozone on days 1, 2, 4, 9 and 10. Male Long-Evans rats were exposed to either air or ozone (0.4, 0.8 ppm) for 4 hours/day utilizing the aforementioned paradigm or for 2 consecutive days to model an acute exposure. Due to the adaptation response commonly observed with acute ozone exposure, we hypothesized that some phenotypic markers of lung injury would be blunted at 2-weeks while certain molecular alterations would either emerge or persist. Penh, an index of airflow limitation, was significantly increased on the first and second day of ozone exposure. This response was suppressed over the course of the 2-week study. Rats exposed to only 2-days of ozone displayed concentration dependent increases in bronchoalveolar lavage fluid (BALF) albumin and protein, whereas this response was not evident in the 2-week exposure group. BALF neutrophils, on the other hand, were significantly increased at both the 2-day and 2-week timepoints in a concentration-dependent manner. After 2-days of ozone, genes associated with angiogenesis (Ace, Cdh5, Flt1) and cell metabolism (Ldhb and Pdk1) were altered but did not persist to 2-weeks. Despite the blunted effect in Penh and protein leakage, differences in genes involved with glucocorticoid signaling (Hsd11b1 and Tsd22d3) and inflammation (Il1r1, Cxcl2, Arg1) were observed in ozone exposed rats. Interestingly, dual specificity phosphatase 1 (Dusp1), which is associated with the negative regulation of both cell proliferation and inflammation, was significantly reduced at both 2-days and 2-weeks of 0.8 ppm ozone only. Reductions in Dusp1 was not observed at 0.4 ppm at either time point. Collectively, these analyses suggest that changes in the glucocorticoid and immune systems persist after 2 weeks of episodic ozone exposure, which may underlie the mixed adaptive response observed. Continued perturbation of these systems may be key in understanding the associations with chronic ozone exposure and cardiopulmonary disease. This abstract does not reflect U.S. EPA policy.