Attenuation of acute lung injury caused by hind-limb ischemia-reperfusion injury by butyrolactone anti-inflammatory agent FL1003.
OBJECTIVE
Activation of systemic inflammation after reperfusion of ischemic tissue results in severe acute lung injury. Neutrophil activation and oxygen radical generation have been implicated in the pathogenesis. This study tested the hypothesis that treatment with FL1003, a butyrolactone with in vitro antioxidant properties, will down-regulate this response and abrogate acute lung injury.


METHODS
Male Sprague-Dawley rats (n = 16) were divided into a surgical sham group (n = 4), a group that received 2 hours of ischemia by infrarenal aortic clip followed 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, while pulmonary artery pressures were held between 5 and 12 mm Hg and venous effluent was collected. Bronchoalveolar lavage fluid and both lungs were harvested at death for determination of tissue water content, pulmonary microvascular permeability, and indicators of neutrophil activation 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 microg/mL) compared with sham animals (IVF, 0 mL; Ficoll concentration, 0.08 +/- 0.03 microg/mL). In addition, lung myeloperoxidase activity (0.60 +/- 0.03 vs. 0.12 +/- 0.02 units/g of tissue) and levels of 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) compared with the sham group. In I/R animals treated with FL1003, the IVF requirement (8.5 +/- 1.0 mL), wet weight/dry weight ratio, lung tissue Ficoll concentration (0.21 +/- 0.02 microg/mL), myeloperoxidase concentration (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.


CONCLUSIONS
A pulmonary microvascular permeability defect with pulmonary edema, neutrophil aggregation, and cell membrane damage resulted from ischemia and reperfusion. Treatment of animals with FL1003 significantly attenuated the inflammatory response associated with acute lung injury.
Cohen
S M
SM
Department of Surgery, The New York Hospital-Cornell Medical Center, New York 10021, USA.
Siddiqi
F A
FA
Darakchiev
B
B
Fantini
G A
GA
Hariri
R J
RJ
Barie
P S
PS
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015633:Extravascular Lung Water; D006614:Hindlimb / Q000098:blood supply*; D015227:Lipid Peroxidation; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D008297:Male; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology
D000893:Anti-Inflammatory Agents; C108075:FL 1003; D015107:4-Butyrolactone