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OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM)
Citation:
Roberts, E. S., R Jaskot, J. E. Richards, AND K L. Dreher. OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM). Presented at Society of Toxicology, Nashville, TN, March 17-21, 2002.
Description:
OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM). E S Roberts1, R Jaskot2, J Richards2, and K L Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC and the 2US Environmental Protection Agency, NHEERL, RTP, NC.
Epidemiological reports suggest that PM is associated with increased rates of cardiopulmonary-related morbidity and mortality. In vitro studies have demonstrated insights into the mechanism of lung injury caused by PM. To further understand the mechanism of PM injury, we studied the in vivo effects of residual oil fly ash (ROFA) exposure on MAPK activation. The MAPK cascade regulates the activity of specific nuclear transcription factors that control genes involved in cell growth, differentiation, apoptosis, and inflammation. A 2 2 factorial arrangement of treatments was used in a randomized design (n=26 male Sprague Dawley rats, 60-90 d of age). Factors included: 1) pre-treatment with either an intraperitoneal (IP) injection of 500 mg/kg dimethlythiourea (DMTU) or saline, thirty minutes prior to instillation (IT) and 2) IT with 0.5 mg/rat ROFA or saline. Bronchoalveolar lavage fluid was obtained at 24h for determination of cytotoxicity and inflammation. ROFA increased lactate dehydrogenase and induced neutrophilia at 24h post-exposure (P < 0.05). IP pre-treatment with DMTU inhibited both the cytotoxicity and neutrophilia (P < 0.05). Sixty-three male Sprague Dawley rats (60-90 d of age) were then randomly assigned as previously described and whole lung samples were collected for analysis at 1h, 3h, and 24h. ROFA increased p-ERK levels at 3h and 24h (P < 0.05). These increases were attenuated by DMTU pretreatment (P < 0.01). DMTU inhibited the ROFA induced p-ERK activity increase at 24h (P < 0.01). The inhibition of ROFA-induced injury, MAPK expression and MAPK activity by DMTU provides strong evidence that generation of oxidative stress is critical to ROFA-induced cytotoxicity. These data link in vitro and in vivo results and demonstrate an oxidative mechanism operating through molecular signaling pathways by which environmental factors cause lung injury. (This abstract does not reflect EPA policy.)