Inhibition of c-Jun NH2-terminal kinase or extracellular signal-regulated kinase improves lung injury.
BACKGROUND
Although in vitro studies have determined that the activation of mitogen-activated protein (MAP) kinases is crucial to the activation of transcription factors and regulation of the production of proinflammatory mediators, the roles of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in acute lung injury have not been elucidated.


METHODS
Saline or lipopolysaccharide (LPS, 6 mg/kg of body weight) was administered intratracheally with a 1-hour pretreatment with SP600125 (a JNK inhibitor; 30 mg/kg, IO), or PD98059 (an MEK/ERK inhibitor; 30 mg/kg, IO). Rats were sacrificed 4 hours after LPS treatment.


RESULTS
SP600125 or PD98059 inhibited LPS-induced phosphorylation of JNK and ERK, total protein and LDH activity in BAL fluid, and neutrophil influx into the lungs. In addition, these MAP kinase inhibitors substantially reduced LPS-induced production of inflammatory mediators, such as CINC, MMP-9, and nitric oxide. Inhibition of JNK correlated with suppression of NF-kappaB activation through downregulation of phosphorylation and degradation of IkappaB-alpha, while ERK inhibition only slightly influenced the NF-kappaB pathway.


CONCLUSIONS
JNK and ERK play pivotal roles in LPS-induced acute lung injury. Therefore, inhibition of JNK or ERK activity has potential as an effective therapeutic strategy in interventions of inflammatory cascade-associated lung injury.
Lee
Hui Su
HS
Department of Physiology, Division of Cell Biology, Ewha Medical Research Institute, Ewha Womans University College of Medicine, 911-1 Mok-6-dong, Yangcheon-ku, Seoul 158-056, Korea. huisulee@hanmail.com
Kim
Hee Jae
HJ
Moon
Chang Sook
CS
Chong
Young Hae
YH
Kang
Jihee Lee
JL
D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000008:administration & dosage*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D000873:Anthracenes; D005419:Flavonoids; D008070:Lipopolysaccharides; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one