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Airways Hyperresponsiveness Following a Single Inhalation Exposure to Doxorubicin-Induced Heart Failure Prevents Airways Transition Metal-Rich Particulate Matter in Hypertensive Rats
Citation:
HAZARI, M. S., N. HAYKAL-COATES, D. W. WINSETT, D. L. COSTA, AND A. FARRAJ. Airways Hyperresponsiveness Following a Single Inhalation Exposure to Doxorubicin-Induced Heart Failure Prevents Airways Transition Metal-Rich Particulate Matter in Hypertensive Rats. Presented at Annual American Thoracic Society, San Diego, CA, May 15 - 20, 2009.
Impact/Purpose:
This study describes the effects of a single exposure to synthetic ROFA, in particular the potentiation of airways responsiveness to methacholine. This study examines the effects of heart failure due to doxorubicin treatment on ROFA-induced airways hyperresponsiveness.
Description:
Exposure to particulate matter (PM) air pollution results in airways hyperresponsiveness (AHR), however it also results in adverse cardiovascular effects, particularly in individuals with underlying cardiovascular disease. The impact of pre-existing cardiac deficit on PM-induced airway hyperresponsiveness has not been fully examined. These experiments were designed to determine if exposure to increasing concentrations of PM causes a concentration-dependent increase in AHR in untreated spontaneously hypertensive (SH) rats or SH rats treated with the anti-neoplastic drug, doxorubicin (DOX), which elicits heart failure. Rats were anesthetized and surgically implanted with radiotelemeters for the continuous monitoring of heart rate (HR) and electrocardiogram (ECG). Following recovery, rats were exposed once by nose-only inhalation for 4 hours to 3.5 mg/m3, 1.0 mg/m3 or 0.45 mg/m3 of a synthetic particulate matter (dried salt solution, MSO4) consisting of Fe, Ni and V sulfates and that is similar in composition to a well-studied residual oil fly ash. A separate group of rats received 5mg/kg DOX or vehicle intraperitoneally once a week for 2 weeks prior to being exposed to 3.5 mg/m3 MSO4. Intravenous methacholine (MCh) challenge was performed on each animal one day after exposure. MCh (2, 4, 8, 16, 32, 64, 128ug/kg) caused a dose-dependent increase in lung resistance (RL) and decrease in dynamic compliance (Cdyn) in control rats, which was significantly potentiated in rats exposed to 1mg/m3 or 3.5 mg/m3 MSO4 but not 0.5 mg/m3. DOX treatment, but not vehicle, produced ECG and HR changes, and arrhythmogenesis which were consistent with heart failure. Pretreatment with DOX also reduced responsiveness to MCh in both air and MSO4 exposed rats resulting in no significant difference between these two groups unlike that observed in vehicle-treated rats. Experiments with Wistar-Kyoto (WKY) rats, a strain with normal blood pressure, are currently being performed for comparison. In conclusion, exposure to a certain threshold concentration of MSO4 is necessary to produce AHR in the SH rat. Additionally, DOX-induced heart failure in SH rats depresses cardiopulmonary responses to such an extent that airway hyperresponsiveness to PM insult is no longer possible. These findings suggest that the value of airway responsiveness data after PM inhalation may have to be reassessed in the context of heart failure (This abstract does not reflect EPA policy.)