ATTENUATION OF ACUTE LUNG INJURY CAUSED BY HINDLIMB ISCHEMIA-REPERFUSION INJURY BY BUTYROLACTONE ANTIINFLAMMATORY AGENT FL1003

Objective: Activation of systemic inflammation after reperfusion of is chemic tissue results in severe acute lung injury, Neutrophil activati on and oxygen radical generation have been implicated in the pathogene sis. This study tested the hypothesis that treatment with FL1003, a bu tyrolactone with in vitro antioxidant properties, will down-regulate t his response and abrogate acute lung injury. Methods: Male Sprague-Daw ley rats (n = 16) were divided into a surgical sham group (n = 4), a g roup that received 2 hours of ischemia by infrarenal aortic clip follo wed by 1 hour of reperfusion (n = 7), and an ischemia-reperfusion (I/R ) group that received FL1003 100 mg/kg intravenously before ischemia ( n = 5), After reperfusion, the heart and lungs were excised en bloc in an isolated lung perfusion apparatus for 1.5 hours of perfusion, whil e pulmonary artery pressures were held between 5 and 12 mm Hg and veno us effluent was collected, Bronchoalveolar lavage fluid and both lungs were harvested at death for determination of tissue water content, pu lmonary microvascular permeability, and indicators of neutrophil activ ation and tissue oxidation. Results: After I/R, there were significant (p < 0.05) increases in intravenous fluid (IVF) requirements (18 +/- 1.2 mL) to maintain hemodynamic stability, wet weight/dry weight ratio of lung tissue, and isolated-lung lavage Ficoll concentrations (0.58 +/- 0.02 mu g/mL) compared with sham animals (IVF, 0 mL; Ficoll concen tration, 0.08 +/- 0.03 mu g/mL). In addition, lung myeloperoxidase act ivity (0.60 +/- 0.03 vs, 0.12 +/- 0.02 units/g of tissue) and levels o f lipid-conjugated dienes (0.042 +/- 0.012 vs, 0.018 +/- 0.006 optical density of 233 nm (OD233)/mL) were significantly higher (p < 0.05) co mpared with the sham group. In I/R animals treated with FL1003, the IV F requirement (8.5 +/- 1.0 mt), wet weight/dry weight ratio, lung tiss ue Ficoll concentration (0.21 +/- 0.02 mu g/mL), myeloperoxidase conce ntration (0.217 +/- 0.02 units/g), and lipid-conjugated diene levels ( 0.012 +/- 0.005 OD233/mL) were all significantly lower (p < 0.05) than after untreated I/R. Conclusion: A pulmonary microvascular permeabili ty defect with pulmonary edema, neutrophil aggregation, and cell membr ane damage resulted from ischemia and reperfusion. Treatment of animal s with FL1003 significantly attenuated the inflammatory response assoc iated with acute lung injury.