Sm. Cohen et al., ATTENUATION OF ACUTE LUNG INJURY CAUSED BY HINDLIMB ISCHEMIA-REPERFUSION INJURY BY BUTYROLACTONE ANTIINFLAMMATORY AGENT FL1003, The journal of trauma, injury, infection, and critical care, 43(2), 1997, pp. 247-252
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.