Time course for inhibition of lipopolysaccharide-induced lung injury by genistein: relationship to alteration in nuclear factor-kappaB activity and inflammatory agents.
OBJECTIVE
This study determined the time course for inhibition of lipopolysaccharide-induced acute lung injury following a single dose of genistein. In addition, the study investigated whether a multiple dosing schedule with genistein retained the inhibitory effects on acute lung injury, nuclear factor-kappaB activation, and production of nuclear factor-kappaB-dependent inflammatory agents, such as matrix metalloproteinase-9 and nitric oxide.


METHODS
Prospective, randomized, laboratory study.


METHODS
Experimental laboratory at a university.


METHODS
Rats weighing 280-300 g.


METHODS
Saline or lipopolysaccharide (6 mg/kg of body weight) administered intratracheally with a single dose of genistein (50 mg/kg) or a multiple dosing schedule with genistein (16 mg/kg every 6 hrs for 2 days with lipopolysaccharide treatment at 24 hrs after the first administration of genistein).


RESULTS
A 2-hr pretreatment with genistein (a single dose) inhibited biochemical lung injury variables as well as neutrophil infiltration with a maximal inhibition at 4 hrs after lipopolysaccharide treatment. These inhibitory effects of genistein declined with time and were no longer significant by 14-24 hrs after lipopolysaccharide treatment. The multiple dosing schedule with genistein retained significant inhibitory effects on biochemical lung injury variables and the number of neutrophils in the bronchoalveolar lavage fluid at 24 hrs after lipopolysaccharide treatment compared with a single pretreatment with genistein. The multiple dosing schedule with genistein also enhanced the inhibition of induced nuclear factor-kappaB activity as well as matrix metalloproteinase-9 activity and nitric oxide production at 24 hrs after lipopolysaccharide treatment.


CONCLUSIONS
This study reports the time course of the inhibitory effects of a single genistein pretreatment on acute lung injury with the maximal effects at 4 hrs after lipopolysaccharide treatment. However, a multiple dosing schedule with genistein retained the inhibitory effect on acute lung injury at 24 hrs after lipopolysaccharide treatment. The mechanisms by which genistein exerts an inhibitory effect on acute lung injury may involve the suppression of nuclear factor-kappaB activation, matrix metalloproteinase-9 activity, and NO production.
Kang
Jihee Lee
JL
Department of Physiology, Ewha Medical Research Center, Ewha Woman's University College of Medicine, Seoul, Korea. jihee@mm.ewha.ac.kr
Lee
Hye Won
HW
Lee
Hui Su
HS
Pack
In Soon
IS
Castranova
Vincent
V
Koh
Younsuck
Y
D000818:Animals; D019833:Genistein / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D019833:Genistein; D020780:Matrix Metalloproteinase 9