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Blood Pressure Interventions Affect Acute and Four-Week Diesel Exhaust Induced Pulmonary Injury in Healthy and Hypertensive Rats
Citation:
SCHLADWEILER, M., T. Krantz, D. W. DAVIES, A. D. Ledbetter, J. H. Shannahan, D. Carlin, J. E. RICHARDS, R. Thomas, AND U. P. KODAVANTI. Blood Pressure Interventions Affect Acute and Four-Week Diesel Exhaust Induced Pulmonary Injury in Healthy and Hypertensive Rats. Presented at American Thoracic Society conference, New Orleans, LA, May 14 - 19, 2010.
Impact/Purpose:
This Abstract examined the effect of exhaust and gas-phase components on pulmonary injury in healthy and hypertensive rats. Rats were rnade hypotensive or hypertensrve by pharmacological intervention. Pulmonary inflammation occurred with diesel exhaust which was reduced in rats by lowering blood pressure.
Description:
Rationale: We recently showed that inhalation exposure of normotensive Wistar Kyoto (WKY) rats to whole diesel exhaust (DE) elicits changes in cardiac gene expression that broadly mimics expression in spontaneously hypertensive (SH) rats without DE. We hypothesized that pharmacological manipulation of blood pressure in SH and WKY rats will alter DE-induced pulmonary injury compared to non-treated controls. Methods: Male WKY (12-14 wks old) rats were treated with either hydralazine or N-nitroL- arginine methy-ester hydrochloride (L-NAME) while SH rats were treated with hydralazine (150 mg/L) in drinking water for 10 days pre exposure (i.e., day -10), during exposure, and until necropsy. At exposure day 1, all rats were exposed to either filtered air, gas-phase components of DE or freshly-generated DE (2000 f.lg/m3) 5hours/day x 5days/week x 4 consecutive weeks or for two days only. Systolic blood pressure was monitored using tail-cuff methodology at days -10,0,2, and at 3-4 week. Lung injury and inflammation were assessed at day 2 and 4 week in bronchoalveolar lavage (BAL) fluid. Results: Hydralazine reduced blood pressure in SH while L-NAME increased blood pressure in WKY rats. The blood pressure effects of drugs observed at day 0, and day 2, were more prominent following 4 week exposure. Gas-phase or DE effects on blood pressure were not clearly apparent with tail-cuff methodology. Whole DE, and also gasphase, elicited a small degree of inflammation and pulmonary protein leakage in BAL in both SH and WKY which was apparent only following acute exposure. Hydralazine treatment reduced acute gas-phase and DE-induced protein leakage and inflammation in SH and WKY rats. Both DE and gas-phase components increased the levels of BAL fluid y-glutamyl transferase (GGT) activity, a marker of pulmonary cell injury and oxidative stress, in both strains exposed acutely or for 1 month. Neither hydralazine nor L-NAME affected DE-induced increases in GGT activity in BALF, despite increased BALF protein leakage in L-NAME-treated air-exposed WKY rats. Conclusion: Reducing blood pressure by hydralazine decreases pulmonary inflammation and protein leakage caused by acute DE exposure in SH rats, whereas, increasing blood pressure with L-NAME in WKY enhances this leakage similar to that of control SH at baseline. Our data provides insight into how DE or gas-phase components might induce pulmonary injury/inflammation and how alterations in blood pressure via pharmacological interventions may alter this inflammatory response in healthy and genetically hypertensive rats.