MECHANISTIC AND THERAPEUTIC ASPECTS OF SPIN TRAP INHALATION TO PROTECT THE OBESE LUNG

RAMIREZ DC; SANDRA E GOMEZ-MEJIBA

DENVER

Congreso; ATS2011; 2011

AMERICAN THORACIC SOCIETY

Mechanistic And Therapeutic Aspects Of Spin Trap Inhalation To Protect The "obese Lung"D. C. Ramirez1, S. E. Gomez-Mejiba21Oklahoma Medical Research Foundation, Oklahoma City, OK, 2Oklahoma Medical Research Foundation, Oklahoma CityCorresponding author's email: dariocramirez@yahoo.comLung inflammation caused by inhalation of air pollutants might play a pathogenic role in obesity by increasing systemic inflammation,which is thought to increase the incidence of insulin resistance and cardiovascular diseases in this population. We found that the lungfrom mice fed a high-fat diet for 20 weeks has more neutrophils and myeloperoxidase (MPO) than mice fed a control chow. This led us tohypothesize that inahlation of air pollutants makes the obese lung an important source of systemic inflammation due to local MPO-relatedoxidative processes. Herein we used only lean animals to test whether and how the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide(DMPO) can affect neutrophil homing in the lung of mice exposed to lipopolysaccharide (LPS). We used male B6 mice with acuteintratracheal instillation of either 50 ml of vehicle (saline) or LPS (50, 125, 250, 500 mg/mouse), with fifty ml of DMPO (0.05, 0.25, 0.5, 2.5nmol/mouse) or vehicle intratracheally instilled 1 h before and 23 h after the instillation of LPS. Twenty four h after the LPS instillation, thebronchoalvelolar lavage fluid (BALF), blood and lung tissue were collected. LPS, DMPO or a combination of both at the doses andfollow-up time used did not cause death of animals; however, mice instilled with LPS became cachexic and asthenic. Interestingly, DMPOtreatment greatly improved these conditions. Cytospin preparation and differential cytology of the BALF showed a cell population mainlycomposed of neutrophils which were reduced in a dose-dependent manner by DMPO. LPS increased markers of oxidative stress(carbonyls, nitrotyrosine and chlorotyrosine), inflammation (TNF-a, IL-1b, nitrite/nitrate, and IL-6) and tissue damage (lacticdehydrogenase) in the BALF supernatant, serum and lung tissue homogenates; these changes were prevented by DMPO. Histology of thelung tissue of mice instilled with LPS and DMPO showed increased protein-DMPO nitrone adduct formation along with reduced ICAM-1expression and TNF-a in the lung parenchyma. Protein nitrone adducts also increased in BALF supernatant and serum, indicating thatbecause of its pharmacokinetic properties DMPO might act locally and systemically to trap protein-centered radicals or that proteinstagged with DMPO in the lung can reach systemic circulation. These results suggest that DMPO blocks inflammation caused by endotoxinby trapping protein-centered radicals, suppressing ICAM-1/chemokine expression, and/or blocking further inflammatory effects ofoxidized proteins. Delivery of DMPO into the lung might be a potential preventive therapy against metabolic complications in obesepatients exposed to air pollution. 5R00ES015415-04This abstract is funded by: NIEHS 5R00ES015415-04