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PULMONARY LOCALIZATION AND EXPRESSION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) IN HEALTHY OR HYPERTENSIVE RATS EXPOSED TO PARTICULATE MATTER (PM)
Citation:
Backus, G. S., R. Vincent, AND U P. Kodavanti. PULMONARY LOCALIZATION AND EXPRESSION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) IN HEALTHY OR HYPERTENSIVE RATS EXPOSED TO PARTICULATE MATTER (PM). Presented at American Thoracic Society, Atlanta, GA, May 17-22, 2002.
Description:
PULMONARY LOCALIZATION AND EXPRESSION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) IN HEALTHY OR HYPERTENSIVE RATS EXPOSED TO PARTICULATE MATTER (PM). GS Backus1, R Vincent2, UP Kodavanti2, 1Curriculum in Toxicology, UNC, Chapel Hill; 2NHEERL, ORD, US EPA, Research Triangle Park, NC, USA; 2Environ Health Ctr, Health Canada, Ottawa, Canada.
Rationale: PAI-1 inhibits fibrinolysis and may increase the risk of thrombosis, leading to occlusive cardiovascular disease. Ambient PM including combustion emissions (e.g., residual oil fly ash; ROFA), are associated with hematological changes and may pose a risk to individuals susceptible to cardiovascular disease. Methods: Spontaneously Hypertensive (SH) and normotensive Wistar Kyoto (WKY) rats (~300g) were instilled intratracheally with either saline, ROFA (0.5 mg/rat) or ambient PM from Ottawa Canada (EC-93; 2.5 mg/rat). ROFA contained 5 times more leachable metals than EC-93, thus, the mass concentration for EC-93 was 5 times that of ROFA in order to normalize for metal content. One day following exposure, pulmonary injury, inflammation and expression of PAI-1 were evaluated. Results: Increased neutrophilic inflammation was observed in bronchoalveolar lavage fluid (BALF) from ROFA and EC-93-exposed WKY and SH rats (SH>WKY). Total protein and LDH were elevated in BALF from all PM-exposed groups, indicating lung injury. The extent of lung injury caused by ROFA and EC-93 differed between two rat strains; ROFA being more toxic to SH and EC-93 being more toxic to WKY rats. Western blot analysis of lung homogenates indicated higher baseline levels of PAI-1 in SH compared to WKY rats. ROFA and EC-93 caused similar increases in PAI-1 in WKY rats but the increases differed slightly in SH rats (ROFA>EC-93). Further, the ROFA-induced PAI-1 increase was greater in SH than in WKY rats, whereas the EC-93-induced increase was similar in both strains. Prominent PAI-1 staining was observed by immunohistochemistry in alveolar macrophages and airway epithelium in both ROFA- and EC-93-exposed SH and WKY rats. Conclusions: ROFA and EC-93-induced injury/inflammation appeared to be metal-dependent, and were associated with localized expression of PAI-1 in the lung. Greater susceptibility of SH rats to PAI-1 expression upon ROFA exposure is consistent with the hypothesis that emission derived PM may pose an increased risk of thrombosis in cardiovascular-compromised rats. (This abstract does not reflect US EPA policy.) The National Research Service Award 5 T32 ESO7126, NIEHS, NIH.