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.

TLR4 Signaling Is Coupled to SRC Family Kinase Activation, Tyrosine Phosphorylation of Zonula Adherens Proteins, and Opening of the Paracellular Pathway in Human Lung Microvascular Endothelia

“…1C). Our findings may explain the findings of the previous in vivo studies (72,73). LPS also activates SFKs in a range of host cells and tissues, including monocytes, macrophages, dentritic cells, glioma cells, and rat tail arteries (30, 74 -76).…”

“…Pretreatment of LPS-challenged rats with genistein decreased extravasation of protein and neutrophils into the bronchoalveolar compartment (72,73). Prior PTK inhibition also blocked LPS-induced actin reorganization, intercellular gap formation, and endothelial barrier disruption in vitro (11).…”

Lipopolysaccharide-induced c-Jun NH2-terminal Kinase Activation in Human Neutrophils

“…JNK activation was shown to increase in an LPSinduced model of acute lung injury, which was inhibited by the protein-tyrosine kinase inhibitor genistein (77). Markers of acute lung injury were also decreased in this model.…”

Effects of genistein following fractionated lung irradiation in mice

“…Genistein inhibits protein kinase activity and blocks activation of the transcription factor NF-κB, a critical mediator of immune and inflammatory responses [141][142][143][144]. Genistein has been reported to reduce acute lung injury from inflammation after lipopolysaccharide treatment [142,144].…”