title: Genistein prevents nuclear factor-kappa B activation and acute lung injury induced by lipopolysaccharide.
abstract: Protein tyrosine kinase (PTK) inhibitors have been proposed to reduce lung injury and lethal toxicity. The mechanisms responsible for the effects of PTK inhibitors remain obscure. The purpose of the present study was to examine whether genistein, a specific inhibitor of PTK, inhibits nuclear factor-kappa B (NF-kappaB) activation during acute lung injury induced by lipopolysaccharide (LPS) and, if so, to enumerate the effects of inhibition of NF-kappaB activation on LPS-induced proinflammatory gene products, such as cytokine-inducible neutrophil chemoattractant (CINC) and matrix metalloproteinase-9 (MMP-9), as well as neutrophil influx into the lungs. Intratracheal treatment of rats with LPS (6 mg/kg) resulted in increases in total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid and activated DNA-binding activity of NF-kappaB in alveolar macrophages and lung tissue. A 2-h pretreatment with genistein (50 mg/kg, intraperitoneally) inhibited the LPS-induced changes in lung injury parameters and the induction of NF-kappaB activation. Furthermore, these inhibitory effects of genistein correlated with a depression of LPS-induced protein tyrosine phosphorylation (approximately molecular masses of 46, 48, and 54 kD) and phosphorylation of Jun N-terminal kinase (JNK) in lung tissue. Genistein also substantially reduced the LPS-induced CINC production and MMP-9 activity and suppressed neutrophil recruitment. These results suggest that genistein attenuates LPS-induced acute lung responses through inhibition of NF-kappaB activation. In addition, NF-kappaB activation appears to be an important mechanism mediating LPS-induced CINC production and MMP-9 activity and resulting neutrophil recruitment associated with acute lung inflammation and injury.
authors.affiliation: Department of Physiology and Microbiology, Division of Cell Biology, Ewha Medical Research Center, Ewha Womans University College of Medicine, Seoul, Korea. jihee@mm.ewah.ac.kr
authors.forename: J L
authors.initials: JL
authors.lastname: Kang
authors.forename: H W
authors.initials: HW
authors.lastname: Lee
authors.forename: H S
authors.initials: HS
authors.lastname: Lee
authors.forename: I S
authors.initials: IS
authors.lastname: Pack
authors.forename: Y
authors.initials: Y
authors.lastname: Chong
authors.forename: V
authors.initials: V
authors.lastname: Castranova
authors.forename: Y
authors.initials: Y
authors.lastname: Koh
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics; D004926:Escherichia coli; D019833:Genistein / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006131:Growth Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; D014443:Tyrosine; D019833:Genistein; D007770:L-Lactate Dehydrogenase; D011505:Protein-Tyrosine Kinases; D020780:Matrix Metalloproteinase 9