Pulmonary and Vascular Effects of Acute Ozone Exposure in Diabetic Rats Fed an Atherogenic Diet

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.

Impact/Purpose

Two important contributors to vascular disease, diabetes mellitus and atherosclerosis, are also potential risk factors of air pollution-induced cardiovascular effects. The goal of this study was to examine how these underlying conditions in rodent models may exacerbate pulmonary and vascular responses to a prototypic air pollutant, ozone. We found that diabetic rats had a more prolonged vascular leakage response compared to Wistar rats, irrespective of diet. The atherogenic diet increased circulating total leukocytes in both strains and increased several inflammatory cytokines, suggesting increased systemic inflammation. This effect on cytokines was more pronounced in Wistar rats and was modestly exacerbated by ozone. GK rats fed normal diet had no vasoconstriction response to ozone, whereas Wistar rats were vasocontricted following ozone exposure. The high cholesterol diet nearly abolished this response to ozone in Wistar rats. Changes in vascular contractility differences could be explained by aortic eNOS expression differences. These data demonstrate that both diabetes and high cholesterol diet may independently exacerbate specific effects of inhaled pollutants and contribute to pulmonary and vascular disease susceptibility.

Citation

Snow, S., A. Henriquez, L. Thompson, C. Fisher, Mette C. Schladweiler, C. Wood, AND U. Kodavanti. Pulmonary and Vascular Effects of Acute Ozone Exposure in Diabetic Rats Fed an Atherogenic Diet. Academic Press Incorporated, Orlando, FL, 415(115430):1, (2021). [DOI: 10.1016/j.taap.2021.115430]

DOI: Pulmonary and Vascular Effects of Acute Ozone Exposure in Diabetic Rats Fed an Atherogenic Diet