The spontaneously hypertensive rat as a model of human cardiovascular disease: Evidence of exacerbated cardiopulmonary injury and oxidative stress from inhaled emission particulate matter

Cardiovascular disease is considered a probable risk factor of particulate matter (PM)-related mortality and morbidity. It was hypothesized that rats with hereditary systemic hypertension and underlying cardiac disease would be more susceptible than healthy normotensive rats to pulmonary injury from inhaled residual oil fly ash (ROFA) PM. Eight spontaneously hypertensive ( SH) and eight normotensive Wistar-Kyoto (WKY) rats (12-13 weeks old) were i mplanted with radiotelemetry transmitters on Day -10 for measurement of ele ctrocardiographic (ECG) waveforms. These and other nonimplanted rats were e xposed to filtered air or ROFA (containing leachable toxic levels of metals ) on Day 0 by nose-only inhalation (ROFA, 15 mg/m(3) x 6 h/day x 3 days). E CGs were monitored during both exposure and nonexposure periods. At 0 or 18 h post-ROFA exposure, rats were assessed for airway hyperreactivity, pulmo nary and cardiac histological lesions, bronchoalveolar lavage fluid (BALF) markers of lung injury, oxidative stress, and cytokine gene expression. Com parisons were made in two areas: (1) underlying cardiopulmonary complicatio ns of control SH rats in comparison to control WKY rats; and (2) ROFA-induc ed cardiopulmonary injury/inflammation and oxidative burden. With respect t o the first area, control air-exposed SH rats had higher lung and left vent ricular weights when compared to age-matched WKY rats. SH rats had hyporeac tive airways to acetylcholine challenge. Lung histology revealed the presen ce of activated macrophages, neutrophils, and hemorrhage in control SH rats . Consistently, levels of BALE protein, macrophages, neutrophils, and red b lood cells were also higher in SH rats. Thiobarbituric acid-reactive materi al in the PALE of air-exposed SH rats was significantly higher than that of WKY rats. Lung inflammation and lesions were mirrored in the higher basal levels of pulmonary cytokine mRNA expression. Cardiomyopathy and monocytic cell infiltration were apparent in the left ventricle of SH rats, along wit h increased cytokine expression. ECG demonstrated a depressed ST segment ar ea in SH rats. With regard to the second area of comparison (ROFA-exposed r ats), pulmonary histology indicated a slightly exacerbated pulmonary lesion s including inflammatory response to ROFA in SH rats compared to WKY rats a nd ROFA-induced increases in BALF protein and albumin were significantly hi gher in SH rats than in WKY rats. In addition, ROFA caused an increase in P ALE red blood cells in SH rats, indicating increased hemorrhage in the alve olar parenchyma. The number of alveolar macrophages increased more dramatic ally in SH rats following ROFA exposure, whereas neutrophils increased simi larly in both strains. Despite greater pulmonary injury in SH rats, ROFA-in duced increases in BALE GSH, ascorbate, and uric acid were attenuated when compared to WKY rats. ROFA inhalation exposure was associated with similar increases in pulmonary mRNA expression of IL-6, cellular fibronectin, and g lucose-6-phosphate dehydrogenase (relative to that of beta-actin) in both r at strains. The expression of MIP-2 was increased in WKY but attenuated in SH rats. Thus, SH rats have underlying cardiac and pulmonary complications. When exposed to ROFA, SH rats exhibited exacerbated pulmonary injury, an a ttenuated antioxidant response, and acute depression in ST segment area of ECC, which is consistent with a greater susceptibility to adverse health ef fects of fugitive combustion PM. This study shows that the SH rat is a pote ntially useful model of genetically determined susceptibility with pulmonar y and cardiovascular complications.